Uracil derivatives, and antitumor effect potentiator and antitumor agent containing the same

ABSTRACT

The invention relates to novel uracil derivatives having excellent inhibiting effects of human derived thymidine phosphorylase and anti-tumor activity. The pharmaceutical compositions, anti-tumor potentiators, antitumor agents containing such novel compounds, and a process for their preparation and use is described. The novel compounds satisfy the general formula (1): ##STR1##

This is a Divisional Application of Parent application Ser. No.08/737,677, filed Nov. 21, 1996 now U.S. Pat. No. 5,744,475.

TECHNICAL FIELD

This invention relates to novel uracil derivatives having excellentinhibitory effects on human-derived thymidine phosphorylase, and also toantitumor effect potentiators and antitumor agents containing same.

BACKGROUND ART

Unnatural pyrimidine nucleosides showing antitumor activities, such as5-fluoro-2'-deoxyuridine and 5-trifluoromethyl-2'-deoxyuridine, havealready known to have strong in vitro activities [Cancer Research, 18,335 (1958); 22, 815 (1962); 28, 2529 (1968); Proceedings of the Societyfor Experimental Biology and Medicine, 97, 470 (1958)].

However, these compounds are known to be promptly decomposed andinactivated in vitro by pyrimidine nucleoside phosphorylase which arefound in the liver, the small intestine and the like [Cancer Research,32, 247 (1972); Japanese Journal of Cancer and Chemotherapy, 8, 262(1981); 8, 1548 (1981)], so that none of them have been found to bringabout satisfactory clinical antitumor effects [Cancer ChemotherapyReports Part 1, 55, 205 (1971); Physicians' Desk Reference, 32, 1387(1978)].

With a view to preventing the inactivation, research have hence beenconducted to develop inhibitors for pyrimidine nucleoside phosphorylase,and some strong inhibitors have been reported. Incidentally, there aretwo types of pyrimidine nucleoside phosphorylases, that is, uridinephosphorylase and thymidine phosphorylase. It has been reported thaturidine phosphorylase is a primary enzyme in selenodonts such as miceand rats while thymidine phosphorylase is a principal enzyme in humanand the like [Japanese Journal of Cancer and Chemotherapy, 8, 262(1981)]. Potentiating the antitumor effects in human therefore requiresan inhibitor for thymidine phosphorylase rather than an inhibitor foruridine phosphorylase.

However, a great majority of inhibitors which have been reported to dateselectively exhibit inhibitory activities against uridine phosphorylaseand show practically no activities against thymidine phosphorylase.Reported to date as exceptions, in other words, as inhibitors forthymidine phosphorylase are 6-amino-5-bromouracil and 6-aminothymine[Biochemical Pharmacology, 29, 1059 (1980)], 6-amino-5-chlorouracil and3-cyano-2,6-dihydroxypyridine [Japanese Patent Application Laid-Open(Kokai) No. SHO 63-250324], acyclothymidine [Japanese Patent ApplicationLaid-Open (Kokai) No. HEI 5-213761], and the like. Their inhibitoryactivities are however not sufficient.

Further, human thymidine phosphorylase has recently been found to be thesame as PD-ECGF (Platelet Derived Endothelial Cell Growth Factor) whichis a human endogenous angiogenic factor [Nature, 356, 668 (1992)].Accordingly, a thymidine phosphorylase inhibitor can inhibitangiogenesis which is closely associated with malignancy of pathomassuch as solid tumors, rheumatism and diabetic retinopathy, and is usefulas a therapeutic for these diseases.

In addition, 5-trifluoromethyl-2'-deoxyuridine also has antiviralactivities and is used as an eye drop for herpetic keratitis [Science,145 (3632), 585 (1964); American Journal of Ophthalmology, 73, 932(1972)]. Phosphorylase inhibitors are also expected to have utility asenhancers for antiviral activities and effects.

An object of the present invention is therefore to provide a novelcompound which has excellent inhibitory effects on human-derivedthymidine phosphorylase and is useful as an antitumor effect potentiatorand an antitumor agent.

With the foregoing circumstances in view, the present inventors haveproceeded with extensive research. As a result, it has been found that auracil derivative represented by the below-described formula (1) hasexcellent inhibitor effects on human-derived thymidine phosphorylase,leading to the completion of the present invention.

DISCLOSURE OF THE INVENTION

This invention relates to a uracil derivative represented by thefollowing formula (1'): ##STR2## wherein R¹ represents a chlorine,bromine or iodine atom or a cyano or lower alkyl group; and R²represents a 4-8 membered heterocyclic group having 1-3 nitrogen atoms,which may be substituted by one or more lower alkyl, imino, hydroxyl,hydroxymethyl, methanesulfonyloxy, amino or nitro groups; an amidinothiogroup, one or more of the hydrogen atom(s) on one or both of thenitrogen atoms of which may each be substituted by a lower alkyl group;a guanidino group, one or more of the hydrogen atom(s) on one, two orall of the nitrogen atoms of which may each be substituted by a loweralkyl or cyano group; a (lower alkyl)amidino group; an amino group, oneor both of the hydrogen atoms on the nitrogen atom of which may each besubstituted by a lower alkyl group; a group --CH₂ N(R^(a))R^(b) in whichR^(a) and R^(b) may be the same or different and each represents ahydrogen atom or a lower alkyl group or R^(a) and R^(b) may form apyrrolidine ring together with the nitrogen atom to which R^(a) andR^(b) are bonded; a group --NH--(CH₂)_(m) --Z in which Z represents anamino group, one or both of the hydrogen atoms on the nitrogen atom ofwhich may each be substituted by a lower alkyl group, or a cyano group,and m stands for an integer of from 0 to 3; a group NR^(c) (CH₂)_(n)--OH in which R^(c) represents a hydrogen atom or a lower alkyl group,and n stands for a natural number of from 1 to 4; a group --X--Y inwhich X represents S or NH, and Y represents a 2-imidazolin-2-yl,2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or2-benzimidazolyl group which may be substituted by one or more loweralkyl groups; or a ureido or thioureido group, one or more of thehydrogen atom(s) on one or both of the nitrogen atoms of which may eachbe substituted by a lower alkyl group, with the proviso that R¹ and R²are not a bromine atom and an amino group, respectively, at the sametime; or a salt thereof.

With respect to 5-bromo-4-aminomethyluracil which has a bromine atom asR¹ and an amino group as R² in the formula (1'), a synthesis process ofits hydrochloride salt has been reported [Acta Poloniae Pharmaceutica,27(4), 329 (1970)], but its inhibitory effects on human-derivedthymidine phosphorylase have not been known.

Accordingly, the present invention relates to a pharmaceuticalcomprising, as an active ingredient, a uracil derivative represented bythe following formula (1): ##STR3## wherein R¹ represents a chlorine,bromine or iodine atom or a cyano or lower alkyl group; and R²represents a 4-8 membered heterocyclic group having 1-3 nitrogen atoms,which may be substituted by one or more lower alkyl, imino, hydroxyl,hydroxymethyl, methanesulfonyloxy, amino or nitro groups; an amidinothiogroup, one or more of the hydrogen atom(s) on one or both of thenitrogen atoms of which may each be substituted by a lower alkyl group;a guanidino group, one or more of the hydrogen atom(s) on one, two orall of the nitrogen atoms of which may each be substituted by a loweralkyl or cyano group; a (lower alkyl)amidino group; an amino _group, oneor both of the hydrogen atoms on the nitrogen atom of which may each besubstituted by a lower alkyl group; a group --CH₂ N(R^(a))R^(b) in whichR^(a) and R^(b) may be the same or different and each represents ahydrogen atom or a lower alkyl group or R^(a) and R^(b) may form apyrrolidine ring together with the nitrogen atom to which R^(a) andR^(b) are bonded; a group --NH--(CH₂)_(m) --Z in which Z represents anamino group, one or both of the hydrogen atoms on the nitrogen atom ofwhich may each be substituted by a lower alkyl group, or a cyano group,and m stands for an integer of from 0 to 3; a group NR^(c) (CH₂)_(n)--OH in which R^(c) represents a hydrogen atom or a lower alkyl group,and n stands for a natural number of from 1 to 4; a group --X--Y inwhich X represents S or NH, and Y represents a 2-imidazolin-2-yl,2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or2-benzimidazolyl group which may be substituted by one or more loweralkyl groups; or a ureido or thioureido group, one or more of thehydrogen atom(s) on one or both of the nitrogen atoms of which may eachbe substituted by a lower alkyl group; or a salt thereof.

The present invention also relates to an antitumor effect potentiatorfor an antitumor agent containing a 2'-deoxypyrimidine nucleoside, whichcomprises as an active ingredient the uracil derivative represented bythe formula (1) or the salt thereof.

In addition, the present invention is concerned with an antitumor agentcomprising the uracil derivative represented by the formula (1) or thesalt thereof and a 2'-deoxypyrimidine nucleoside.

The present invention is also concerned with a pharmaceuticalcomposition comprising the uracil derivative represented by the formula(1) or the salt thereof and a pharmaceutically acceptable carrier.

The present invention is also concerned with an antitumor agentcomprising the uracil derivative represented by the formula (1) or thesalt thereof, a 2'-deoxypyrimidine nucleoside and a pharmaceuticallyacceptable carrier.

Further, the present invention pertains to use of the uracil derivativerepresented by the formula (1) or the salt thereof as a pharmaceutical.

The present invention also pertains to use of the uracil derivativerepresented by the formula (1) or the salt thereof as an antitumoreffect potentiator for an antitumor agent containing a2'-deoxypyrimidine nucleoside.

The present invention also pertains to use of the uracil derivativerepresented by the formula (1) or the salt thereof for the production ofan antitumor agent comprising the uracil derivative represented by theformula (1) or the salt thereof and a 2'-deoxypyrimidine nucleoside.

Moreover, the present invention relates to a method for potentiatingantitumor effect of an antitumor agent containing a 2'-deoxypyrimidinenucleoside, which comprises administering to a patient an effectiveamount of the uracil derivative represented by formula (1) or the saltthereof.

The present invention also relates to a therapeutic method of a cancer,which comprises administering to a patient effective amounts of theuracil derivative represented by formula (1) or the salt thereof and a2'-deoxypyrimidine nucleoside.

BEST MODE FOR CARRYING OUT THE INVENTION

Illustrative of the lower alkyl group represented by R¹ and R² in theformulas (1) and (1') are linear or branched alkyl groups having 1 to4,carbon atoms. Specific examples include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl groups. Among these, amethyl group is particularly preferred.

Illustrative of the 4-8 membered heterocyclic group containing 1-3nitrogen atoms and represented by R² are 1-azetidinyl, 1-pyrrolidinyl,2-pyrrolin-1-yl, 3-pyrrolin-1-yl, 1-pyrrolyl, 1-pyrazolidinyl,2-pyrazolin-1-yl, 3-pyrazolin-1-yl, 4-pyrazolin-1-yl, 1-pyrazolyl,1-imidazolidinyl, 2-imidazolin-1-yl, 3-imidazolin-1-yl,4-imidazolin-1-yl, 1-imidazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl,piperidino, 1-piperazyl, morpholino, 1-perhydroazepinyl and1-perhydroazocinyl groups. Further, these heterocyclic groups maycontain one or two substituent groups on their rings. Examples of suchsubstituent groups include lower alkyl, imino, hydroxyl, hydroxymethyl,methanesulfonyloxy, amino and nitro groups. Specific examples of theheterocyclic group which may contain such substituent groups include1-azetidinyl, 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl,2-iminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,2-hydroxymethylpyrrolidin-1-yl, 3-methanesulfonyloxypyrrolidin-1-yl,3-aminopyrrolidin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl,2-imino-3-pyrrolin-1-yl, 1-pyrrolyl, 1-pyrazolidinyl,2-methylpyrazolidin-1-yl, 4-iminopyrazolidin-1-yl, 2-pyrazolin-1-yl,3-pyrazolin-1-yl, 2-methyl-3-pyrazolin-1-yl, 5-imino-3-pyrazolin-1-yl,4-pyrazolin-1-yl, 2-methyl-4-pyrazolin-1-yl, 3-imino-4-pyrazolin-1-yl,1-pyrazolyl, 1-imidazolidinyl, 3-methylimidazolidin-1-yl,2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl,2-imino-3-ethylimidazolidin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl,2-imidazolin-1-yl, 3-imidazolin-1-yl, 4-imidazolin-1-yl,3-methyl-4-imidazolin-1-yl, 2-imino-4-imidazolin-1-yl,2-imino-3-methyl-4-imidazolin-1-yl, 2-imino-3-ethyl-4-imidazolin-1-yl,2-imino-3-isopropyl-4-imidazolin-1-yl, 1-imidazolyl,2-methylimidazol-1-yl, 2-nitroimidazol-1-yl, 4-nitroimidazol-1-yl,1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 3-nitro-1,2,4-triazol-1-yl,piperidino, 1-piperazyl, 4-methylpiperazin-1-yl, morpholino,1-perhydroazepinyl and 1-perhydroazocinyl groups. Preferred examplesinclude 1-azetidinyl, 1-pyrrolidinyl, 2-iminopyrrolidin-1-yl,2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl,2-imino-3-ethylimidazolidin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl,2-imidazolin-1-yl, 2-imino-3-methyl-4-imidazolin-1-yl,2-.imino-3-ethyl-4-imidazolin-1-yl and 1-imidazolyl groups.

Illustrative of the amidinothio group represented by R², one or more ofthe hydrogen atom(s) on one or both of the nitrogen atoms of which mayeach be substituted by a lower alkyl group, are those in which one tothree of the three hydrogen atoms on the nitrogen atoms of an amidinogroup may be substituted by the above lower alkyl group or groups.Especially, amidinothio, N¹ -methylamidinothio and N¹,N²-dimethylamidinothio groups are preferred.

Illustrative of the guanidino group, one or more of the hydrogen atom(s)on one, two or all of the nitrogen atoms of which may each besubstituted by a lower alkyl or cyano group, are those in each of whichone to four of the four hydrogen atoms in a guanidino group may besubstituted by the above lower alkyl or cyano group or groups.Especially, 1-guanidino, 1-methylguanidino, 3-methylguanidino,2,3-dimethylguanidino and 2-cyano-3-methylguanidino groups arepreferred.

Illustrative of the (lower alkyl)amidino group are those formed ofamidino groups and the lower alkyl groups bonded thereto, respectively.Of these, an acetoamidino group is preferred.

Illustrative of the amino group, one or both of the hydrogen atoms onthe nitrogen atom of which may each be substituted by a lower alkylgroup, are those in each of which one or two of the two hydrogen atomson an amino group may be substituted by the above lower alkyl group orgroups. Of these, amino, N-methylamino, N,N-dimethylamino, N-ethylamino,N,N-diethylamino, N-propylamino and N-isopropylamino groups arepreferred.

Preferred examples of the group represented by --CH₂ N(R^(a))R^(b)include N-methylaminomethyl, N,N-dimethylaminomethyl and1-pyrrolidinylmethyl groups.

Preferred examples of the group represented by --NH--(CH₂)_(m) --Zinclude N,N-dimethylhydrazino, N-(2-aminoethyl)amino,N-(2-(N,N-dimethyl)aminoethyl)amino, N-(3-aminopropyl)amino andN-(2-cyanoethyl)amino groups.

Preferred examples of the group NR^(c) (CH₂)_(n) --OH includeN-(2-hydroxyethyl)-N-methylamino, N-(3-hydroxypropyl)amino andN-(4-hydroxybutyl)amino groups.

Preferred examples of the group represented by --X--Y include2-imidazolin-2-thio, 2-imidazolin-2-amino, imidazol-2-thio,1-methylimidazol-2-thio, 1,2,4-triazol-3-thio, pyrimidin-2-thio andbenzimidazol-2-thio groups.

Preferred examples of the ureido or thioureido group, one or more of thehydrogen atom(s) on one or both of the nitrogen atoms of which may eachbe substituted by a lower alkyl group, include ureido and3-methylthioureido groups.

Preferred examples of the group represented by R² in the formula (1)include 4-8 membered heterocyclic groups having 1-3 nitrogen atoms,which may each be substituted by one or more lower alkyl, imino,hydroxyl, hydroxymethyl, methanesulfonyloxy, amino or nitro groups;amidinothio groups, one or more of the hydrogen atom(s) on one or bothof the nitrogen atoms of each of which may each be substituted by alower alkyl group; guanidino groups, one or more of the hydrogen atom(s)on one, two or all of the nitrogen atoms of each of which may each besubstituted by a lower alkyl or cyano group; or (lower alkyl)amidinogroups.

Among the groups represented by R², preferred specific examples include1-azetidinyl, 1-pyrrolidinyl, 2-iminopyrrolidin-1-yl,2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl,2-imino-3-ethylimidazolidin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl,2-imidazolin-1-yl, 2-imino-3-methyl-4-imidazolin-1-yl,2-imino-3-ethyl-4-imidazolin-1-yl, 1-imidazolyl, amidinothio, N¹-methylamidinothio, N¹,N² -dimethylamidinothio, 1-guanidino,1-methylguanidino, 3-methylguanidino, 2,3-dimethylguanidino andacetoamidino groups.

Preferred examples of the uracil derivative represented by the formula(1) include those containing a chlorine or bromine atom or a cyano groupas R¹ and a 1-pyrrolidinyl, 1-azetidinyl, 2-iminopyrrolidin-1-yl,2-iminoimidazolidin-1-yl, 1-imidazolyl, amidinothio or 1-guanidino groupas R².

Examples of the salt of the uracil derivative (1) can include, but arenot limited to, acid-addition salts and/or base salts which have beenobtained by causing pharmacologically acceptable acids or basiccompounds to act respectively. Examples of these acid addition saltsinclude salts with inorganic acids such as hydrochloric acid, sulfuricacid, phosphoric acid and hydrobromic acid as well as salts with organicacids such as oxalic acid, maleic acid, fumaric acid, malic acid,tartaric acid, citric acid, benzoic acid, acetic acid, p-toluenesulfonicacid and methanesulfonic acid, with the salt with hydrochloric acid orp-toluenesulfonic acid being preferred. Exemplary base salts includesalts with alkali metals and alkaline earth metals such as sodium,potassium, magnesium and calcium as well as salts with amines such asammonia, methylamine, dimethylamine, piperidine, cyclohexylamine andtriethylamine.

Particularly preferred specific examples of the uracil derivative (1) orits salt include:

5-chloro-6-(1-pyrrolidinylmethy)uracil,

5-bromo-6-(1-pyrrolidinylmethyl)uracil,

5-chloro-6-(1-azetidinylmethyl)uracil,

5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride,

5-bromo-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride,

5-cyano-6-(1-(2-iminopyrrolidinyl)methyl)uracil,

5-chloro-6-(1-(2-iminoimidazolidinyl)methyl) uracil,

5-bromo-6-(1-(2-iminoimidazolidinyl)methyl) uracil,

5-chloro-6-(1-imidazolylmethyl)uracil hydrochloride,

2-(5-chlorouracil-6-ylmethyl)isothiourea hydrochloride,

2-(5-cyanouracil-6-ylmethyl)isothiourea hydrochloride,

5-chloro-6-(1-guanidino)methyluracil hydrochloride.

The uracil derivative (1) of the present invention can be prepared, forinstance, in accordance with the following Processes A to M, usingvarious compounds as raw materials: ##STR4## wherein R¹ has the samemeaning as defined above, l stands for a number of 1 or 2, and R³represents 4-8 membered heterocyclic group having 1-3 nitrogen atoms,which may be substituted by one or more lower alkyl, imino, hydroxyl,hydroxymethyl, amino or nitro groups; a group --NH--(CH₂)_(m) --Z inwhich Z represents an amino group, one or both of the hydrogen atoms onthe nitrogen atom of which may each be substituted by a lower alkylgroup, or a cyano group, and m stands for an integer of from 0 to 3; ora group NR^(c) (CH₂)_(n) --OH in which R^(c) represents a hydrogen atomor a lower alkyl group, and n stands for a natural number of from 1 to4.

(Step 1)

The compound represented by the formula (1-a) can be prepared byreacting the compound represented by the formula (2), which is obtainedby the below-described preparation processes (Process N) and (ProcessO), and the known compound represented by the formula (3), which isdisclosed in literature [Journal of Organic Chemistry, 32, 738 (1967);Journal of Medicinal Chemistry, 15, 415 (1972)] in a suitable solvent inthe presence or absence of a basic compound.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; amines such as pyridine andtriethylamine; alkyl ketones such as acetone, methyl ethyl ketone andmethyl isobutyl ketone; alcohols such as methanol, ethanol and propanol;and water.

Illustrative basic compounds include organic basic compounds, e.g.,tertiary amines such as triethylamine, diisopropylethylamine,tributylamine, pyridine, dimethylaminopyridine and1,8-diazabicyclo-[5.4.0]undec-7-ene; and inorganic basic compounds,e.g., alkali metal carbonates such as sodium carbonate and potassiumcarbonate, alkali metal bicarbonates such as sodium bicarbonate andpotassium bicarbonate, alkali metal hydroxides such as sodium hydroxideand potassium hydroxide, alkali metals such as sodium and potassium,alkali metal alkoxides such as sodium methoxide, sodium ethoxide andpotassium t-butoxide, and alkali metal hydrides such as sodium hydride.

As proportions of the raw materials, it is preferred to use the compoundof the formula (3) in an amount of from 1 to 10 mole equivalents,preferably from 1 to 5 mole equivalents and the basic compound in anamount of from 1 to 5 mole equivalents, both per mole of the compound ofthe formula (2). The reaction temperature may range from 0° C. to theboiling point of the solvent or so, preferably from 0° C. to 80° C. Thereaction time may range from 0.1 to 48 hours, preferably from 0.5 to 24hours.

When R³ is a heterocycle having a hydroxyl group in the compoundrepresented by the formula (1-a), the hydroxyl group can be convertedfurther into a methanesulfonyloxy group by a usual method. Describedspecifically, the methanesulfonyloxy derivative can be obtained by usingN,N-dimethylformamide, dimethylsulfoxide, dichloromethane, pyridine orthe like as a solvent, triethylamine, pyridine, dimethylaminopyridine orthe like as a basic compound and methanesulfonyl chloride as amesylating agent, employing the mesylating agent in an amount of from 1to 2 mole equivalents and the basic compound in an amount of from 1 to 5mole equivalents, both per mole of the compound of the formula (1-a),and reacting them at a reaction temperate of from 0° C. to the boilingpoint of the solvent or so for 0.5 to 48 hours. ##STR5## wherein R¹ hasthe same meaning as defined above.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 2)

The compound represented by the formula (1-a') can be prepared byreacting the compound represented by the formula (5), which is obtainedby reacting the compound of the formula (2-a) and ethylenediamine (4) inaccordance with Process A, with cyanogen bromide in a suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; alcohols such as methanol, ethanol andpropanol; and water.

In this reaction, it is preferred to conduct the reaction by usingcyanogen bromide in an amount of from 1 to 2 mole equivalents per moleof the compound of the formula (5). The reaction temperature may rangefrom 0° C. to the boiling point of the solvent or so, preferably from 0°C. to 80° C. The reaction time may range from 0.5 to 48 hours,preferably from 1 to 24 hours. ##STR6## wherein R¹ has the same meaningas defined above.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 3)

The compound represented by the formula (1-b') can be prepared byreacting the compound represented by the formula (5) with trimethylorthoformate in a suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; alcohols such as methanol, ethanol andpropanol; and acetic acid, formic acid and water.

In this reaction, it is preferred to use the trimethyl orthoformate inan amount of from 1 to 2 mole equivalents per mole of the compound ofthe formula (5). The reaction temperature may range from 0° C. to theboiling point of the solvent or so, preferably from 80° C. to 130° C.The reaction time may range from 0.5 to 12 hours, preferably from 1 to 4hours. ##STR7## wherein R¹ has the same meaning as defined above, and Arepresents CH or N.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 4)

The compound represented by the formula (1-b") can be prepared byreacting the compound represented by the formula (2-a) with the compoundrepresented by the formula (6) in a suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; alkyl ketones such as acetone, methylethyl ketone and methyl isobutyl ketone; alcohols such as methanol,ethanol and propanol; and water.

In this reaction, it is preferred to use the compound of the formula (6)in an amount of from 1 to 2 mole equivalents per mole of the compound ofthe formula (2-a). The reaction temperature may range from 0° C. to theboiling point of the solvent or so, preferably from 50° C. to 120° C.The reaction time may range from 0.5 to 72 hours, preferably from 1 to48 hours. ##STR8## wherein R¹ has the same meaning as defined above, andR⁴ and R⁵ may be the same or different and each represents a hydrogenatom or a lower alkyl group.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 5)

The compound represented by the formula (1-c) can be prepared byreacting the compound represented by the formula (2-a) with thecommercially-available compound represented by the formula (7) in asuitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; alkyl ketones such as acetone, methylethyl ketone and methyl isobutyl ketone; alcohols such as methanol,ethanol and propanol; and water.

For this reaction, it is preferred to use the compound of the formula(7) in an amount of from 1 to 2 mole equivalents per mole of thecompound of the formula (2-a). The reaction temperature may range from0° C. to the boiling point of the solvent or so, preferably from 50° C.to 120° C. The reaction time may range from 0.5 to 24 hours, preferablyfrom 1 to 8 hours. ##STR9## wherein R¹ and l have the same meanings asdefined above, R⁶ and R⁷ may be the same or different and eachrepresents a hydrogen atom or a lower alkyl group, and R⁸ s eachrepresents a hydrogen atom or a lower alkyl group or two R⁸ s representsa 2-imidazolin-2-yl group together with the nitrogen atom to which theyare bonded.

More specifically, the individual steps shown in the above reactionscheme can be practiced as will be described hereinafter.

(Step 6)

The compound represented by the formula (9) can be prepared by reactingthe compound represented by the formula (2) with thecommercially-available compound represented by the formula (8) in asuitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as tetrahydrofuran anddioxane; alcohols such as methanol, ethanol and propanol; and water.

In this reaction, it is preferred to use the compound of the formula (8)in an amount of from 1 to 50 mole equivalents, preferably from 1 to 10mole equivalents per mole of the compound of the formula (2). Thereaction temperature may range from 0° C. to the boiling point of thesolvent or so, preferably from 0° C. to 80° C. The reaction time mayrange from 0.5 to 168 hours, preferably from 1 to 96 hours.

The compound of the formula (9) available by the above reaction can beused in Step 7 with or without isolation.

(Step 7)

The compound represented by the formula (1-d) can be prepared byreacting the compound represented by the formula (9-a) and the knowncompound represented by the formula (10), which is disclosed inliterature [Analytical Biochemistry, 57, 310 (1974)] or is commerciallyavailable, in a suitable solvent in the presence or absence of a basiccompound.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as tetrahydrofuran anddioxane; alcohols such as methanol, ethanol and propanol; and water.

Illustrative basic compounds include inorganic basic compounds, e.g.,alkali metal carbonates such as sodium carbonate and potassiumcarbonate, alkali metal bicarbonates such as sodium bicarbonate andpotassium bicarbonate, alkali metal hydroxides such as sodium hydroxideand potassium hydroxide, alkali metals such as sodium and potassium,alkali metal alkoxides such as sodium methoxide, sodium ethoxide andpotassium t-butoxide, and alkali metal hydrides such as sodium hydride.

In this reaction, it is preferred to use the compound of the formula(10) in an amount of from 1 to 2 mole equivalents and the basic compoundin an amount of from 1 to 5 mole equivalents, both per mole of thecompound of the formula (9-a). The reaction temperature may range from0° C. to the boiling point of the solvent or so, preferably from 0° C.to 80° C. The reaction time may range from 0.5 to 48 hours, preferablyfrom 1 to 24 hours. ##STR10## wherein R¹ and R⁶ have the same meaningsas defined above, and R⁹ represents a lower alkyl group.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 8)

The compound represented by the formula (1-e) can be prepared byreacting the compound represented by the formula (9-a) and the compoundrepresented by the formula (11), which is disclosed in literature[Organic Syntheses Collective, 1, 5 (1941)], in a suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as tetrahydrofuran anddioxane; alcohols such as methanol, ethanol and propanol; and water.

In this reaction, it is preferred to use the compound of the formula(11) in an amount of from 1 to 2 mole equivalents per mole of thecompound of the formula (9-a). The reaction temperature may range from0° C. to the boiling point of the solvent or so, preferably from 0° C.to 80° C. The reaction time may range from 0.5 to 48 hours, preferablyfrom 1 to 24 hours. ##STR11## wherein R^(1a) represents a chlorine,bromine or iodine atom, and R³ and l have the same meanings as definedabove.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 9)

The compound represented by the formula (1-a") can be prepared byreacting the compound represented by the formula (12), which is obtainedin accordance with the below-described preparation process (Process P),with a chlorinating agent, brominating agent or iodating agent in asuitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as tetrahydrofuran anddioxane; alcohols such as methanol, ethanol and propanol; and aceticacid, formic acid, concentrated sulfuric acid and water.

Illustrative of the chlorinating agent are chlorine,N-chlorosuccinimide, sulfuryl chloride and sodium hypochlorite.

Illustrative of the brominating agent are bromine, N-bromosuccinimideand pyridiniumbromide perbromide.

Illustrative of the iodating agent are iodine ad N-iodosuccinimide.

In this reaction, it is preferred to use the chlorinating agent,brominating agent or iodating agent in an amount of from 1 to 3 moleequivalents per mole of the compound of the formula (12). The reactiontemperature may range from 0° C. to the boiling point of the solvent orso, preferably from 0° C. to 80° C. The reaction time may range from 0.5to 48 hours, preferably from 1 to 12 hours. ##STR12## wherein R¹ has thesame meaning as defined above.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 10)

The compound represented by the formula (1-b"') can be prepared byreacting the compound represented by the formula (9-b) and2,5-dimethoxytetrahydrofuran (13) in a suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; alcohols such as methanol, ethanol andpropanol; and acetic acid, formic acid, concentrated sulfuric acid andwater.

In this reaction, it is preferred to use 2,5-dimethoxytetrahydrofuran(13) in an amount of from 1 to 5 mole equivalents, preferably from 1 to2 mole equivalents per mole of the compound of the formula (9-b). Thereaction temperature may range from 0° C. to the boiling point of thesolvent or so, preferably from 0° C. to 120° C. The reaction time mayrange from 0.5 to 48 hours, preferably from 1 to 24 hours. ##STR13##wherein R¹ has the same meaning as defined above, and R¹⁰ represents a2-imidazolin-2-yl, 2-imidazolyl, 1,2,4-triazol-3-yl,1-methylimidazol-2-yl, 2-pyrimidyl or 2-benzimidazolyl group.

More specifically, the step shown in the above reaction formula can bepracticed as will be described 5 hereinafter.

(Step 11)

The compound represented by the formula (1-f) can be prepared byreacting the compound represented by the formula (2-a) and thecommercially-available compound represented by the formula (14) in asuitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; alkyl ketones such as acetone, methylethyl ketone and methyl isobutyl ketone; alcohols such as methanol,ethanol and propanol; and water.

In this reaction, it is preferred to use the compound of the formula(14) in an amount of from 1 to 3 mole equivalents per mole of thecompound of the formula (2-a). The reaction temperature may range from0° C. to the boiling point of the solvent or so, preferably from 0° C.to 100° C. The reaction time may range from 0.5 to 24 hours, preferablyfrom 1 to 8 hours. ##STR14## wherein R¹ and R⁶ have the same meanings asdefined above, and R¹¹ represents a lower alkyl group.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 12)

The compound represented by the formula (1-g) can be prepared byreacting the compound represented by the formula (1-g) and the compoundrepresented by the formula (15) in a suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; and ethers such as tetrahydrofuran anddioxane.

In this reaction, it is preferred to use the compound of the formula(15) in an amount of from 1 to 2 mole equivalents per mole of thecompound of the formula (9-a). The reaction temperature may range from0° C. to the boiling point of the solvent or so, preferably from 0° C.to 80° C. The reaction time may range from 0.5 to 48 hours, preferablyfrom 1 to 24 hours. ##STR15## wherein R¹ has the same meaning as definedabove.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 13)

The compound represented by the formula (17) can be prepared by reactingthe compound represented by the formula (9-b) and S,S'-dimethylN-cyanodithioiminocarbonate (16), which is a compound commerciallyavailable on the market, in a suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; amines such as pyridine andtriethylamine; alkyl ketones such as acetone, methyl ethyl ketone andmethyl isobutyl ketone; alcohols such as methanol, ethanol and propanol;and water.

In this reaction, it is preferred to use S,S'-dimethylN-cyanodithioiminocarbonate (16) in an amount of from 1 to 5 moleequivalents, preferably from 1 to 2 mole equivalents per mole of thecompound of the formula (9-b). The reaction temperature may range from0° C. to the boiling point of the solvent or so, preferably from 60° C.to 130° C. The reaction time may range from 0.5 to 24 hours, preferablyfrom 1 to 8 hours.

The compound of the formula (17) available by the above reaction can beused in Step 14 with or without isolation.

(Step 14)

The compound represented by the formula (1-d') can be prepared byreacting the compound represented by the formula (17) and methylamine ina suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; alcohols such as methanol, ethanol andpropanol; and water.

In this reaction, it is preferred to use methylamine in an amount offrom 1 to 100 mole equivalents per mole of the compound of the formula(17). The reaction temperature may range from 0° C. to the boiling pointof the solvent or so, preferably from 0° C. to 80° C. The reaction timemay range from 0.5 to 24 hours, preferably from 1 to 8 hours. ##STR16##wherein R¹ has the same meaning as defined above.

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 15)

The compound represented by the formula (1-g') can be prepared byreacting the compound represented by the formula (9-b) and urea (18) ina suitable solvent.

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such asdichloromethane and chloroform; amines such as pyridine andtriethylamine; alkyl Aft ketones such as acetone, methyl ethyl ketoneand methyl isobutyl ketone; alcohols such as methanol, ethanol andpropanol; and water.

In this reaction, it is preferred to use urea in an amount of from 1 to2 mole equivalents per mole of the compound of the formula (9-b). Thereaction temperature may range from 0° C. to the boiling point of thesolvent or so. The reaction time may range from 0.5 to 48 hours,preferably from 1 to 24 hours.

The compounds represented by the formula (2), which are raw materialsfor the above-described Process A, Process B, Process D, Process E,Process F and Process J, can be prepared from various compounds as rawmaterials, for example, in accordance with Process N or Process O whichwill be described below. On the other hand, 6-chloromethylthymine can beprepared by the process disclosed in literature [Journal of the AmericanChemical Society, 35, 596 (1913)]. ##STR17## wherein Q represents achlorine, bromine or iodine atom, and l stands for 1 or 2.

(Step 16)

The compound represented by the formula (2-b) can be prepared followingStep 9 of Process H, using as a raw material 6-chloromethyluracil, acommercially-available compound, or 6-(2-chloroethyl)uracil, a compoundalready known from Journal of Heterocyclic Chemistry, 16, 239 (1979).##STR18##

More specifically, the step shown in the above reaction formula can bepracticed as will be described hereinafter.

(Step 17)

The compound (22) can be prepared by reacting ethyl2-chloro-N-cyanoacetoimidate (20) disclosed in literature [Journal ofOrganic Chemistry, 28, 1816 (1963)] and ethyl cyanoacetate (21) in asuitable solvent in the presence of a basic compound in accordance withthe process disclosed in literature [Journal of the Chemical SocietyChemical Communications, 350 (1974)].

No particular limitation is imposed on the solvent to be used hereinsofar as it takes no part in the reaction. Examples of the solventinclude aprotic polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide andhexamethylphosphoric triamide; ethers such as tetrahydrofuran anddioxane; alcohols such as methanol, ethanol and propanol; and water.

Illustrative basic compounds include inorganic basic compounds, e.g.,alkali metal carbonates such as sodium carbonate and potassiumcarbonate, alkali metal bicarbonates such as sodium bicarbonate andpotassium bicarbonate, alkali metal hydroxides such as sodium hydroxideand potassium hydroxide, alkali metals such as sodium and potassium,alkali metal alkoxides such as sodium methoxide, sodium ethoxide andpotassium t-butoxide, and alkali metal hydrides such as sodium hydride.

In this reaction, it is preferred to use ethyl cyanoacetate (21) in anamount of from 1 to 2 mole equivalents per mole of ethyl2-chloro-N-cyanoacetoimidate (20). The reaction temperature may rangefrom 0° C. to the boiling point of the solvent or so, preferably from 0°C. to 80° C. The reaction time may range from 0.5 to 48 hours,preferably from 1 to 24 hours.

The compound of the formula (22) available by the above reaction can beused in Step 18 with or without isolation.

(Step 18)

The compound (2-c) can be prepared by reacting the compound (22) withsodium hydroxide in water in accordance with the process disclosed inliterature [Journal of the Chemical Society Chemical Communications, 350(1974)].

In the above reaction, it is preferred to use sodium hydroxide in anamount of from 1 to 100 mole equivalents per mole of the compound (22).The reaction temperature may range from 0° C. to the boiling point ofthe solvent or so, preferably from 0° C. to 50° C. The reaction time mayrange from 0.5 to 24 hours, preferably from 1 to 6 hours.

Further, the compound according to the present invention represented bythe formula (12), which is the raw material for Process H, can beprepared, for example, by the below-described Process P, using variouscompounds as raw materials. ##STR19## wherein R³ and l have the samemeanings as defined above. (Step 19)

The compound represented by the formula (12) can be prepared followingStep 1 of Process A, using 6-chloromethyluracil or6-(2-chloroethyl)uracil (19).

The compounds (1), which have been obtained by Process A, Process B.Process C, Process D, Process E, Process F, Process G, Process H,Process I, Process J, Process K, Process L and Process M, can be usedafter isolating and purifying them by conventional separation means, forexample, column chromatography, recrystallization, vacuum distillationor the like.

The uracil derivative (1) or its salt according to the presentinvention, which has been obtained as described above, has excellenthuman thymidine phosphorylase inhibiting effects and is useful as aneffective ingredient for an antitumor effect potentiator or an antitumoragent.

The uracil derivative represented by the formula (1) or its salt isuseful as an antitumor effect potentiator for an antitumor agentcontaining a 2'-deoxypyrimidine nucleoside. Here, illustrative of the2'-deoxypyrimidine nucleoside are 5-trifluoromethyl-2'-deoxyuridine,thymidine, 5-fluoro-2'-deoxyuridine, prodrug derivatives [for example,PCT International Publication No. WO95/18138] of5'-fluoro-2'-deoxyuridine, and 5-aza-2'-deoxycytidine. Of these,particularly preferred are 5-trifluoromethyl-2'-deoxyuridine and5-fluoro-2'-deoxyuridine.

To use as an antitumor effect potentiator, the uracil derivative or itssalt (1) formulated into one of dosage unit forms and an antitumor agentalso formulated by itself into one of various dosage unit forms andcontaining a 2'-deoxypyrimidine nucleoside can be administeredseparately or at the same time.

As an alternative, the uracil derivative (1) or its salt can also beadministered as an antitumor agent containing same and a2'-deoxypyrimidine nucleoside after formulating it into one of variousdosage unit forms. In this case, no particular limitation is imposed onthe proportions of the 2'-deoxypyrimidine nucleoside and the uracilderivative (1) or its salt. It is however preferred to use the latter inan amount of from 0.1 to 500 moles or so, especially from 0.2 to 10moles or so per mole of the former.

Upon using the antitumor effect potentiator and antitumor agentaccording to the present invention as therapeutics for malignant tumorsof mammals including human, they can be formulated into variouspharmacological dosage forms depending on the purposes of treatments.Specifically, they can be formulated into oral preparations such astablets, coated tablets, pills, powders, granules, capsules, solutions,suspensions and emulsions; and parenteral preparations such asinjections, suppositories, ointments and plasters. These dosablepreparations can each be formulated by a commonly formulation methodgenerally known in the present field of art while using apharmaceutically acceptable carrier or the like.

Upon formulation into the form of tablets, usable examples of carriersinclude excipients such as lactose, sucrose, sodium chloride, glucose,urea, starch, calcium carbonate, kaolin, crystalline cellulose andsilicic acid; binders such as water, ethanol, propanol, corn starch,simple syrup, glucose solution, starch solution, gelatin solution,carboxymethyl cellulose, shellac, methyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, potassium phosphate andpolyvinyl pyrrolidone; disintegrators such as dried starch, sodiumalginate, powdered agar, powdered laminarin, sodium bicarbonate, calciumcarbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic acid monoglyceride, starch and lactose; disintegrationsuppressors such as sucrose, stearic acid, cacao butter and hydrogenatedoils; absorbefacients such as quaternary ammonium bases and sodiumlauryl sulfate; humectants such as glycerin and starch; adsorbents suchas starch, lactose, kaolin, bentonite and colloidal silicic acid; andlubricants such as purified talc, stearate salts, powdered boric acidand polyethylene glycol. Further, tablets may be formed into thoseapplied with conventional coatings as needed, for example, sugar-coatedtablets, gelatin-coated tablets, enteric-coated tablets, film-coatedtablets, double-layer tablets and multi-layer tablets.

Examples of carriers usable upon formulation into the form of pillsinclude excipients such as glucose, lactose, starch, cacao butter,hydrogenated vegetable oils, kaolin and talc; binders such as powderedgum arabic, powdered tragacanth, gelatin and ethanol; and disintegratorssuch as laminarin and agar.

Capsules can be formulated by mixing the uracil derivative (1) or itssalt with one or more of the above-exemplified various carriers and thenfilling the resultant mixture in hard gelatin capsules, soft capsules orthe like.

To formulate liquid preparations for oral administration, liquidpreparation for internal use, syrups and elixirs can be formulated bymethods known per se in the art, using taste corrigents, buffers,stabilizers and smell corrigents. Illustrative of the taste corrigentsare sucrose, bitter orange peel, citric acid and tartaric acid,illustrative of the buffers is sodium citrate, and illustrative of thestabilizers are tragacanth gum, gum arabic and gelatin.

As a carrier upon formulation into the form of suppositories, it ispossible to use, for example, polyethylene glycol, cacao butter, ahigher alcohol, an ester of a higher alcohol, gelatin, semisyntheticglyceride or the like.

To formulate injections, it is preferred to sterilize solutions,emulsions or suspensions and to make them isotonic with blood. Usableexamples of diluents upon formulation into the form of these injectionsinclude water, an aqueous lactic acid solution, ethyl alcohol, propyleneglycol, Macrogol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. Inthis case, such pharmaceutical preparations may contain sodium chloride,glucose or glycerin in an amount sufficient to prepare isotonicsolutions. Further, conventional solubilizing aids, buffers, soothingagents, and the like may also be added.

Examples of diluents usable upon formulation into the form of ointments,for example, pastes, creams and gels include white petrolatum, paraffin,glycerin, cellulose derivatives, polyethylene glycol, silicone andbentonite.

For the formulation of a plaster, it is only necessary to coat aconventional backing material with the above-described ointment, cream,gel, paste or the like. Suitable examples of the backing materialinclude woven fabrics or nonwoven fabrics of cotton, rayon or chemicalfibers, and films or foamed sheets of soft PVC, polyethylene orpolyurethane.

To the above-described preparations, a coloring matter, a preservative,a perfume, a corrigent, a sweetening and/or the like as well as anotherpharmaceutical can also be added as needed.

No particular limitations are imposed on the amounts of the2'-deoxypyrimidine nucleoside and the uracil derivative (1) or the saltthereof, which are contained in each preparation according to thepresent invention. In general, however, it is preferred to control thecontent of each of them at about 1 to 70 wt. % in each preparation.

No particular limitation is imposed on the administration method for theeach preparation according to the present invention. An administrationmethod is determined as desired depending on the form of thepreparation, the age, sex and other conditions of the patient, theseverity of a symptom of the patient, and the like. For example, oraladministration is used for tablets, pills, powders, granules capsules,solutions, suspensions and emulsions. Injections are intravenouslyadministered either by themselves or as mixtures with a usual fluidreplacement such as glucose or amino acids, and if necessary, are alsoadministered by themselves intra-arterially, intramuscularly,intracutaneously, subcutaneously or intraperitoneally. Suppositories areadministered intrarectally. Ointments are coated on the skin, the oralmucosa or the like, whereas plasters are applied on the skin.

The dose of the active ingredient in each preparation according to thepresent invention can be suitably chosen depending on the administrationmethod, the age, sex and other conditions of the patient, the severityof the disease, and the like. As a general standard, the dose of the2'-deoxypyrimidine nucleoside may range from about 0.1 to 100 mg/kg/day,preferably from about 0.5 to 50 mg/kg/day, and the dose of the uracilderivative (1) or the salt thereof may range from about 0.01 to 10000mg/kg/day, preferably from about 0.5 to 1000 mg/kg/day. Thesepreparations according to the present invention can each be administeredonce a day or in about 2 to 4 portions in a day.

Malignant tumors curable by the administration of preparations accordingto the present invention are not limited to any particular ones butinclude, for example, esophageal carcinoma, gastric cancer, livercancer, gallbladder and bile duct cancers, pancreas cancer, coloncancer, rectum cancer, head and neck cancers, lung cancer, breastcancer, cervical cancer, ovarian cancer, bladder cancer, prostaticcancer, testis tumor, osteochondroma, skin cancer, malignant lymphoma,leukemia, brain tumor and the like.

EXAMPLES

The present invention will hereinafter be described more specifically bythe following Referential Examples and Examples but shall not be limitedthereto.

[Synthesis of the Compound (2-b) by Process N]

Referential Example 1

Synthesis of 5-chloro-6-chloromethyluracil

To a suspension of 6-chloromethyluracil (163 g) in acetic acid (500 ml),sulfuryl chloride (120 ml) was added dropwise at room temperature over20 minutes, followed by stirring at the same temperature for 3 hours.The reaction mixture was poured into ice water (500 ml), and acrystallized matter was collected by filtration, whereby 182.3 g of thetitle compound were obtained (yield: 92%).

Melting point: 225° C. min. (decomposed).

NMR spectrum (DMSO-d₆) δ: 4.46(2H,s), 11.57(1H,s), 11.71(1H,s).

    ______________________________________                                        Elemental analysis (as C.sub.5 H.sub.4 N.sub.2 O.sub.2 Cl.sub.2):                      C           H      N                                                 ______________________________________                                        Calculated:                                                                              30.80         2.07   14.37                                         Found:     30.85         1.99   14.41                                         ______________________________________                                    

Referential Example 2

Synthesis of 5-bromo-6-chloromethyluracil

A reaction was conducted in a similar manner as Referential Example 1except that N-bromosuccinimide was used instead of sulfuryl chloride,whereby the title compound was obtained in a yield of 70%.

Melting point: 245° C. min. (decomposed).

NMR spectrum (DMSO-d₆) δ: 4.47(2H,s), 11.61(1H,s), 11.66(1H,s).

    ______________________________________                                        Elemental analysis (as C.sub.5 H.sub.4 N.sub.2 O.sub.2 BrCl):                          C           H      N                                                 ______________________________________                                        Calculated:                                                                              25.08         1.68   11.70                                         Found:     24.81         1.67   11.57                                         ______________________________________                                    

Referential Example 3

Synthesis of 5-iodo-6-chloromethyluracil

A reaction was conducted in a similar manner as Referential Example 1except that N-iodosuccinimide was used instead of sulfuryl chloride,whereby the title compound was obtained in a yield of 77%.

Melting point: 225° C. min. (decomposed).

NMR spectrum (DMSO-d₆) δ: 4.49(2H,s), 11.52(1H,s), 11.58(1H,s).

    ______________________________________                                        Elemental analysis (as C.sub.5 H.sub.4 N.sub.2 O.sub.2 ClI):                           C           H      N                                                 ______________________________________                                        Calculated:                                                                              20.96         1.41   9.78                                          Found:     21.10         1.36   9.87                                          ______________________________________                                    

Referential Example 4

Synthesis of 5-chloro-6-(2-chloroethyl)uracil

A reaction was conducted in a similar manner as Referential Example 1except that 6-(2-chloroethyl)uracil was used instead of6-chloromethyluracil, whereby the title compound was obtained in a yieldof 77%.

Melting point: 225° C. min. (decomposed).

NMR spectrum (DMSO-d₆) δ: 3.01(2H,t,J=6.9 Hz), 3.88(2H,t,J=6.9 Hz),11.28(1H,s), 11.60(1H,s).

    ______________________________________                                        Elemental analysis (as C.sub.6 H.sub.6 N.sub.2 O.sub.2 Cl.sub.2.2/5H.sub.2     O):                                                                                   C           H      N                                                 ______________________________________                                        Calculated:                                                                              33.89         3.03   13.18                                         Found:     34.27         3.02   12.75                                         ______________________________________                                    

[Synthesis of the Compound (2-c) by Process O]

Referential Example 5

Synthesis of ethyl 4-chloro-2-cyano-3-ureidocrotonate (22)

A solution of 20 g of ethyl 2-chloro-N-cyanoacetoimidate (20), 16.6 g ofethyl cyanoacetate (21) and 9.28 g of sodium ethoxide in ethanol (350ml) was stirred at room temperature for 3 hours. After the reactionmixture was distilled, 140 ml of 2 N hydrochloric acid were added,followed by stirring under ice cooling for 1 hour. After the reactionmixture was neutralized with a 2 N aqueous solution of sodium hydroxide,the resultant mixture was extracted with ethyl acetate. The extract waswashed with water, dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The residue so obtained waspurified by chromatography on a silica gel column while using gradientelution with hexane-ethyl acetate, whereby 5.66 g of the title compoundwere obtained (yield: 18%).

Melting point: 175-177° C.

NMR spectrum (DMSO-d₆) δ: 1.27(3H,t,J=6.9 Hz), 4.26(2H,q,J=6.9 Hz),5.38(2H,s), 10.05(1H,s).

    ______________________________________                                        Elemental analysis (as C.sub.8 H.sub.10 N.sub.3 O.sub.2 Cl):                           C           H      N                                                 ______________________________________                                        Calculated:                                                                              41.48         4.35   18.14                                         Found:     41.87         4.44   17.78                                         ______________________________________                                    

Referential Example 6

Synthesis of 5-cyano-6-chloromethyluracil (2-b)

Dissolved in 17 ml of a 2 N aqueous solution of sodium hydroxide were3.88 g of the ethyl 4-chloro-2-cyano-ureidocrotonate (22) obtained inReferential Example 5. The resulting mixture was stirred at roomtemperature for 1 hour and under ice cooling, was neutralized with 2 Nhydrochloric acid. A crystallized matter was collected by filtration,whereby 1.16.g of the title compound were obtained (yield: 37%).

Melting point: 229° C. min. (decomposed).

NMR spectrum (DMSO-d₆) δ: 4.45(2H,s), 10.05 (1H,s).

    ______________________________________                                        Elemental analysis (as C.sub.6 H.sub.4 N.sub.3 O.sub.2 Cl.1/10H.sub.2         O):                                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              38.46         2.26   22.43                                         Found:     38.72         2.20   22.07                                         ______________________________________                                    

[Synthesis of the Compound (12) by Process P]

Referential Example 7

Synthesis of 6-(1-pyrrolidinylmethyl)uracil

To a solution of 1.78 g of pyrrolidine in water (20 ml), 1.33 g of6-chloromethyluracil were added. The resulting mixture was stirred atroom temperature for 24 hours and neutralized with acetic acid. Thereaction mixture was then concentrated under reduced pressure. Theresidue so obtained was washed with methanol and then filtered, whereby466 mg of the title compound were obtained (yield: 29%).

Melting point: 176-178° C. min.

NMR spectrum (DMSO-d₆) δ: 1.68-1.76(4H,m), 2.42-2.55(4H,m), 3.49(2H,s),5.44(1H,s), 10.90(2H,br-s).

    ______________________________________                                        Elemental analysis (as C.sub.9 H.sub.13 N.sub.3 O.sub.2.4/5H.sub.2 O):                 C           H      N                                                 ______________________________________                                        Calculated:                                                                              51.57         7.02   20.04                                         Found:     51.59         6.94   19.73                                         ______________________________________                                    

Physical properties of compounds obtained in the following Examples arepresented in Table 1 to Table 20.

[Synthesis of the compound (1-a) by Process A]

Example 1

Synthesis of 5-chloro-6-(1-pyrrolidinylmethyl)uracil (Compound 1)

To a solution of 32.8 g of pyrrolidine in water (300 ml), 30.0 g of the5-chloro-6-chloromethyluracil obtained in Referential Example 1 wereadded. After the resultant mixture was stirred at room temperature for24 hours, an insoluble matter was removed by filtration. The filtratewas concentrated under reduced pressure. The residue so obtained waswashed with methanol and collected by filtration, whereby 14.2 g of thetitle compound were obtained (yield: 40%).

Example 2

Syntheses of Compounds 2 to 21

Compounds 2 to 21, which are shown in Table 1 to Table 3 and Table 11 toTable 13, were synthesized in a similar manner as Example 1 by usingappropriate starting raw materials.

Example 3

Synthesis of5-chloro-6-(1-(3-methanesulfonyloxy)pyrrolidinylmethyl)uracil (Compound22)

To a solution of 702 mg of the5-chloro-6-(1-(3-hydroxy)pyrrolidinylmethyl)uracil (Compound 8), whichhad been obtained in Example 2, in pyridine (5 ml), 350 mg ofmethanesulfonyl chloride were added. After the resultant mixture wasstirred at room temperature for 24 hours, the reaction mixture waspurified by chromatography on a silica gel column (chloroformmethanolelution), whereby 220 mg of the title compound were obtained (yield:24%).

Example 4

Synthesis of 5-chloro-6-(3-nitro-1,2,4-triazol-1-ylmethyl)uracil(Compound 23)

To a solution of 0.88 g of 3-nitro-1,2,4-triazole in a 1 N aqueoussolution of KOH (10 ml), 0.50 g of 5-chloro-6-chloromethyluracil wasadded, followed by heating at 80° C. for 2.5 hours under stirring. Thereaction mixture was neutralized with 6 N hydrochloric acid. Aprecipitate was collected by filtration and then washed with water andmethanol, whereby 510 mg of the title compound were obtained (yield:73%).

Example 5

Syntheses of Compounds 24 to 28

Compounds 24 to 28, which are shown in Table 3 to Table 4 and Table 13to Table 14, were synthesized in a similar manner as Example 4 by usingappropriate starting raw materials.

Example 6

Synthesis of 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracilhydrochloride (Compound 29)

A solution of 5.0 g of 5-chloro-6-chloromethyluracil, 6.14 g of2-iminopyrrolidine and 5.24 g of sodium ethoxide inN,N-dimethylformamide (50 ml) was stirred at room temperature for 14hours. A crystallized matter was collected by filtration and thensuspended in 30 ml of water. After the suspension was neutralized withacetic acid and then washed, an insoluble matter was collected byfiltration and then dissolved in 60 ml of 1 N hydrochloric acid.Activated carbon was added to the resultant solution, followed byfiltration. The filtrate was concentrated under reduced pressure, andthe residue so obtained was washed with ethanol and collected withfiltration, whereby 2.68 g of the title compound were obtained (yield:38%).

Example 7

Synthesis of 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracilp-toluenesulfonate (Compound 30)

A reaction was conducted in a similar manner as Example 6 except thatp-toluenesulfonic acid was used instead of 1 N hydrochloric acid,whereby the title compound was obtained in a yield of 26%.

Example 8

Syntheses of Compounds 31 to 36

Compounds 31 to 36, which are shown in Table 4 to Table 5 and Table 14to Table 15, were synthesized in a similar manner as Example 6 by usingappropriate starting raw materials.

Example 9

Synthesis of 6-N-(2-aminoethyl)aminomethyl-5-chlorouracil (Compound 37)

To a solution of 60 g of anhydrous ethylenediamine in water (200 ml), 39g of the 5-chloro-6-chloromethyluracil obtained in Referential Example 1were added. The resulting mixture was stirred at room temperature for 24hours. A crystallized matter was collected by filtration, whereby 28.35g of the title compound were obtained (yield: 65%).

Example 10

Synthesis of 6-N-(2-aminoethyl)aminomethyl-5-bromouracil (Compound 38)

A reaction was conducted in a similar manner as Example 9 except that5-bromo-6-chloromethyluracil was used instead of5-chloro-6-chloromethyluracil, whereby the title compound was obtainedin a yield of 46%.

Example 11

Synthesis of 6-N-(2-aminoethyl)aminomethyl-5-iodouracil (Compound 39)

A reaction was conducted in a similar manner as Example 9 except that5-iodo-6-chloromethyluracil was used instead of5-chloro-6-chloromethyluracil, whereby the title compound was obtainedin a yield of 69%.

Example 12

Syntheses of Compounds 40 to 43

Compounds 40 to 43, which are shown in Table 5 to Table 6 and Table 15,were synthesized in a similar manner as Example 9 by using appropriatestarting raw materials.

Example 13

Synthesis of 5-chloro-6-(3-hydroxypropylamino)uracil (Compound 44)

To a solution of 580 mg of 3-hydroxypropylamine in water (20 ml), 500 mgof the 5-chloro-6-chloromethyluracil obtained in Referential Example 1were added, followed by stirring at room temperature for 19 hours. Thereaction mixture was concentrated under reduced pressure and a crudeproduct so obtained was purified by chromatography on a silica gelcolumn (chloroform-methanol-triethylamine elution), whereby 70 mg of thetitle compound were obtained (yield: 12%).

Example 14

Syntheses of Compounds 45 and 46

Compounds 45 and 46, which are shown in Table 6 and Table 16, weresynthesized in a similar manner as Example 13 by using appropriatestarting raw materials.

[Synthesis of Compound (1-a') by Process B]

Example 15

Synthesis of 5-chloro-6-(1-(2-iminoimidazolidinyl)methyl)uracil(Compound 47)

To a solution of 3.6 g of cyanogen bromide in water (50 ml), 7.0 g of6-N-(2-aminoethyl)aminomethyl-5-chlorouracil obtained in Example 9 wereadded, followed by stirring at room temperature for 3.5 hours. Acrystallized matter was collected by filtration, washed withN,N-dimethylformamide and then suspended in 50 ml of water. Thesuspension was neutralized with a 1 N aqueous solution of sodiumhydroxide and an insoluble matter was collected, whereby 2.65 g of thetitle compound were obtained (yield: 34%).

Example 16

Syntheses of Compounds 48 and 49

Compounds 48 and 49, which are shown in Table 6 and Table 16, weresynthesized in a similar manner as Example 15 by using appropriatestarting raw materials.

[Synthesis of Compound (1-b) by Process C]

Example 17

Synthesis of 5-chloro-6-(2-imidazolin-1-ylmethyl)uracil hydrochloride(Compound 50)

To a solution of 1.0 g of the6-N-(2-aminoethyl)aminomethyl-5-chlorouracil, which had been obtained inExample 9, in acetic acid (3 ml), 0.56 ml of triethyl orthoformate wasadded, followed by heating for 1 hour under reflux. To the reactionmixture, 0.1 ml of concentrated hydrochloric acid and 2 ml of aceticacid were added. The resultant mixture was then allowed to cool down. Acrystallized matter was collected by filtration and then washed withN,N-dimethylformamide, whereby 220 mg of the title compound wereobtained (yield: 18%).

[Synthesis of Compound (1-b') by Process D]

Example 18

Synthesis of 5-chloro-6-(1-imidazolylmethyl)uracil hydrochloride(Compound 51)

To a solution of 4.3 g of N-acetylimidazole in methanol (100 ml), 5.0 gof 5-chloro-6-chloromethyluracil were added, followed by heating for 2days under reflux. After the reaction mixture was allowed to cool down,a crystallized matter was collected by filtration and then washed with a10% solution of hydrochloric acid in methanol, whereby 4.32 g of thetitle compound were obtained (yield: 64%).

Example 19

Synthesis of 5-chloro-6-(1,2,3-triazol-1-ylmethyl)uracil (Compound 52)

A reaction was conducted in a similar manner as Example 18 except thatN-acetyl-1,2,3-triazole was used instead of N-acetylimidazole, wherebythe title compound was obtained in a yield of 58%.

[Synthesis of Compound (1-c) by Process E]

Example 20

Synthesis of 2-(5-chlorouracil-6-ylmethyl)isothiourea hydrochloride(Compound 53)

To a solution of 140 mg of thiourea in ethanol (3 ml), 300 mg of5-chloro-6-chloromethyluracil were added, followed by heating for 6hours under reflux. After the reaction mixture was allowed to cool down,a crystallized matter was collected by filtration, whereby 337 mg of thetitle compound were obtained (yield: 81%).

Example 21

Syntheses of Compounds 54 to 58

Compounds 54 to 58, which are shown in Table 7 and Table 17, weresynthesized in a similar manner as Example 20 by using appropriatestarting raw materials.

[Synthesis of Compound (9) by Process F]

Example 22

Synthesis of 6-aminomethyl-5-chlorouracil (Compound 59)

To 400 ml of a 25% aqueous solution of ammonia, 10 g of the5-chloro-6-chloromethyluracil obtained in Referential Example 1 wereadded, followed by stirring at room temperature for 4 days. Acrystallized matter was collected by filtration, whereby 7.3 g of thetitle compound were obtained (yield: 81%).

Example 23

Synthesis of 5-chloro-6-N-methylaminomethyluracil (Compound 60)

To 150 ml of a 40% aqueous solution of methylamine, 6 g of the5-chloro-6-chloromethyluracil obtained in Referential Example 1 wereadded. The resulting mixture was stirred at room temperature for 4.5hours and then concentrated under reduced pressure. The residue soobtained was washed with methanol and then collected by filtration,whereby 5.38 g of the title compound were obtained (yield: 92%).

Example 24

Syntheses of Compounds 61 to 67

Compounds 61 to 67, which are shown in Table 8 and Table 17 to Table 18,were synthesized in a similar manner as Example 23 by using appropriatestarting raw materials.

[Synthesis of Compound (1-d) by Process F]

Example 25

Synthesis of 5-chloro-6-(1-guanidino)methyluracil hydrochloride(Compound 68)

Subsequent to addition of 455 mg of 2-methylisothiourea sulfate to 33 mlof a 0.1 N aqueous solution of potassium hydroxide under ice cooling,600 mg of the 6-aminomethyl-5-chlorouracil obtained in Example 22 wereadded, followed by heating for 2 hours at 80° C. under stirring. Afterthe reaction mixture was allowed to cool down, a crystallized matter wascollected by filtration and washed with 2 N hydrochloric acid, whereby287 mg of the title compound were obtained (yield: 33%).

Example 26

Syntheses of Compounds 69 to 72

Compounds 69 to 72, which are shown in Table 9 and Table 18, weresynthesized in a similar manner as Example 25 by using appropriatestarting raw materials.

[Synthesis of Compound (1-e) by Process G]

Example 27

Synthesis of N-(5-chlorouracil-6-ylmethyl)acetamidine hydrochloride(Compound 73)

To a solution of 705 mg of ethyl acetoimidate hydrochloride inN,N-dimethylformamide (12 ml), 500 mg of 6-aminomethyl-5-chlorouracilwere added, followed by stirring at room temperature for 13 hours. Afterthe reaction mixture was allowed to cool down, a crystallized matter wascollected by filtration and then washed with a 10% solution ofhydrochloric acid in methanol, whereby 190 mg of the title compound wereobtained (yield: 26%).

[Synthesis of Compound (1-a") by Process H]

Example 28

Synthesis of 5-bromo-6-(1-pyrrolidinylmethyl)uracil (Compound 2)

To a solution of 1.0 g of the 6-(1-pyrrolidinylmethyl)uracil, which hadbeen obtained in Referential Example 7, in acetic acid (10 ml), 1.0 g ofbromine was added dropwise, followed by stirring at room temperature for20 hours. A crystallized matter was collected by filtration and thenwashed with methanol, whereby 560 mg of the title compound were obtained(yield: 40%). The melting point and NMR spectrum of the thus-obtainedcompound were in full conformity with those of Compound 2 synthesized byProcess A in Example 2.

    ______________________________________                                        Elemental analysis (as C.sub.9 H.sub.12 N.sub.3 O.sub.2 Br):                           C           H      N                                                 ______________________________________                                        Calculated:                                                                              39.44         4.41   15.33                                         Found:     39.48         4.47   15.43                                         ______________________________________                                    

[Synthesis of Compound (1-b"') by Process I]

Example 29

Synthesis of 5-chloro-(1-pyrrolylmethyl)uracil (Compound 74)

To a solution of 500 mg of the 6-aminomethyl-5-chlorouracil, which hadbeen obtained in Example 22, in acetic acid (8 ml), 577 mg of2,5-dimethoxytetrahydrofuran were added, followed by heating at 110° C.for 2 hours under stirring. The temperature of the reaction mixture wascooled back to room temperature. After an insoluble matter was filteredoff, the filtrate was concentrated under reduced pressure. The residueso obtained was purified by chromatography on a silica gel column(chloroform-methanol elution), whereby 155 mg of the title compound wereobtained (yield: 24%).

[Synthesis of Compound (1-f) by Process J]

Example 30

Synthesis of 5-chloro-6-(2-imidazolylthiomethyl)uracil (Compound 75)

A reaction was conducted in a similar manner as Example 20 except that2-mercaptoimidazole was used instead of thiourea, whereby the titlecompound was obtained in a yield of 77%.

Example 31

Syntheses of Compounds 76 to 80

Compounds 76 to 80, which are shown in Table 9 to Table 10 and Table 19,were synthesized in a similar manner as Example 30 by using appropriatestarting raw materials.

[Synthesis of Compound (1-g) by Process K]

Example 32

Synthesis of N-methyl-N'-(5-chlorouracil-6-ylmethyl)thiourea (Compound81)

A suspension of 0.50 g of 5-chloro-6-chloromethyluracil and 0.22 g ofmethyl isothiocyanate in N,N-dimethylformamide (3 ml) was heated at 70°C. for 4 hours under stirring. Water (50 ml) was added to the reactionmixture. A crystallized matter was collected by filtration and thenwashed with water and methanol, whereby 435 mg of the title compoundwere obtained (yield: 61%).

[Synthesis of Compound (1-d') by Process L]

Example 33

Synthesis of N-cyano-N'-methyl-N"(5-chlorouracil-6-ylmethyl)guanidine(Compound 82)

A suspension of 1.0 g of the 6-aminomethyl-5-chlorouracil obtained inExample 22 and 0.926 g of S,S'-dimethyl-N-cyanodithioiminocarbonate inN,N-dimethylformamide (20 ml) was heated at 120° C. for 3.5 hours understirring. The reaction mixture was concentrated under reduced pressure.Methanol was added to the residue, followed by filtration. The filtratewas concentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (chloroform-methanol elution),whereby 190 mg ofN-cyano-N'-(5-chlorouracil-6-ylmethyl)-S-methylisothiourea wereobtained.

Next, 150 mg of theN-cyano-N'-(5-chlorouracil-6-ylmethyl)-S-methylisothiourea weresuspended in ethanol (3 ml), followed by the addition of 2 ml of a 30%solution of methylamine in ethanol. The resulting mixture was heated at50° C. for 3.5 hours under stirring. After an insoluble matter wasfiltered off, the filtrate was allowed to cool back to room temperature.A precipitate from the filtrate was collected by filtration, whereby 12mg of the title compound were obtained (yield: 96%).

[Synthesis of Compound (1-g') by Process M]

Example 34

Synthesis of 5-chloro-6-(ureidomethyl)uracil (Compound 83)

6-Aminomethyl-5-chlorouracil (300 mg) obtained in Example 22 wassuspended in 2 N hydrochloric acid (10 ml), followed by concentrationunder reduced pressure. To the residue, 188 mg of urea and 15 ml ofwater were added, followed by heating for 24 hours under reflux. Afteran insoluble matter was filtered off, the filtrate was allowed to coolback to room temperature. A precipitate was collected by filtration andthen recrystallized from water, whereby 33 mg of the title compound wereobtained (yield: 9%).

                                      TABLE 1                                     __________________________________________________________________________     ##STR20##                                                                                                   Elemental analysis (%)                         Comp'd             m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                             No. R.sup.1                                                                          R.sup.2     Molecular formula                                                                      (%)                                                                              C   H  N                                       __________________________________________________________________________    1   Cl                                                                                ##STR21##  207-209  C.sub.9 H.sub.12 N.sub.3 O.sub.2 Cl                                           40  47.07  (46.97                                                                    5.27  5.36                                                                       18.30   18.15)                          2   Br                                                                                ##STR22##  213-215  C.sub.9 H.sub.12 N.sub.3 O.sub.2 Br                                           60  39.44  (39.54                                                                    4.41  4.44                                                                       15.33   15.49)                          3   I                                                                                 ##STR23##  178 min. (decomp)  C.sub.9 H.sub.12 N.sub.3 O.sub.2                                    17  33.66  (33.73                                                                    3.77  3.89                                                                       13.09   13.05)                          4   CN                                                                                ##STR24##  205 min. (decomp)  C.sub.10 H.sub.12 N.sub.4 O.sub.2                          H.sub.2 O                                                                              17  50.41  (50.70                                                                    5.92  5.57                                                                       23.52   23.29)                          5   CH.sub.3                                                                          ##STR25##  196-198  C.sub.10 H.sub.15 N.sub.3 O.sub.2  1/5H.sub.2                        O        25  56.43  (56.39                                                                    7.29  7.36                                                                       19.74   19.62)                          6   Cl                                                                                ##STR26##  190-191  C.sub.8 H.sub.10 N.sub.3 O.sub.2 Cl                                           40  44.56  (44.34                                                                    4.67  4.72                                                                       19.49   19.35)                          7   Cl                                                                                ##STR27##  220 min. (decomp)  C.sub.11 H.sub.16 N.sub.3 O.sub.2                          Cl        9  51.27  (51.13                                                                    6.26  6.41                                                                       16.30   16.34)                          8   Cl                                                                                ##STR28##  190 min. (decomp)  C.sub.9 H.sub.12 N.sub.3 O.sub.3                                    22  44.00  (44.06                                                                    4.92  5.08                                                                       17.10   16.94)                          __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________     ##STR29##                                                                                                   Elemental analysis (%)                         Comp'd             m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                             No. R.sup.1                                                                         R.sup.2      Molecular formula                                                                      (%)                                                                              C   H  N                                       __________________________________________________________________________     9  Cl                                                                               ##STR30##   165-167  C.sub.10 H.sub.14 N.sub.3 O.sub.3 Cl                                          53  46.25  (46.23                                                                    5.43  5.60                                                                       16.18   15.99)                          10  Cl                                                                               ##STR31##   165-167  C.sub.10 H.sub.14 N.sub.3 O.sub.3 Cl                                          22  46.25  (46.46                                                                    5.43  5.65                                                                       16.18   16.10)                          11  Cl                                                                               ##STR32##   220 min. (decomp)  C.sub.9 H.sub.13 N.sub.4 O.sub.2 Cl                         2HCl1/5H.sub.2 O                                                                      91  33.65  (33.65                                                                    4.83  4.93                                                                       17.44   17.41)                          12  Cl                                                                               ##STR33##   233-236  C.sub.8 H.sub.9 N.sub.4 O.sub.2 Cl                                            99  42.03  (41.72                                                                    3.97  3.86                                                                       24.50   24.10)                          13  Cl                                                                               ##STR34##   195 min. (decomp)  C.sub.10 H.sub.14 N.sub.3 O.sub.2                          Cl       61  49.29  (49.37                                                                    5.79  5.83                                                                       17.24   17.15)                          14  Br                                                                               ##STR35##   215 min. (decomp)  C.sub.10 H.sub.14 N.sub.3 O.sub.2                          Br       30  41.68  (41.70                                                                    4.90  5.00                                                                       14.58   14.54)                          15  Cl                                                                               ##STR36##   205 min. (decomp)  C.sub.10 H.sub.15 N.sub.4 O.sub.2                          Cl        1  46.43  (46.44                                                                    5.84  6.05                                                                       21.66   21.53)                          16  Cl                                                                               ##STR37##   245  C.sub.9 H.sub.12 N.sub.3 O.sub.3 Cl  1/10H.sub.2                         O        78  43.68  (43.68                                                                    4.97  4.81                                                                       16.98   16.89)                          17  Cl                                                                               ##STR38##   200 min. (decomp)  C.sub.11 H.sub.16 N.sub.3 O.sub.2                          Cl       47  51.27  (51.39                                                                    6.26  6.50                                                                       16.30   16.37)                          __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________     ##STR39##                                                                                                       Elemental analysis (%)                     Comp'd                 m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                         No. R.sup.1                                                                         R.sup.2          Molecular formula                                                                      (%)                                                                              C   H  N                                   __________________________________________________________________________    18  Cl                                                                               ##STR40##       175 min. (decomp)  C.sub.12 H.sub.18 N.sub.3                                  O.sub.2 Cl                                                                             46  53.04  (53.03                                                                    6.68  7.03                                                                       15.46   15.39)                      19  Cl                                                                               ##STR41##       270 min. (decomp)  C.sub.10 H.sub.14 N.sub.3                                  O.sub.2 Cl                                                                             14  49.29  (49.00                                                                    5.79  6.02                                                                       17.24   16.90)                      20  Cl                                                                               ##STR42##       250 min. (decomp)  C.sub.9 H.sub.10 N.sub.5                                   O.sub.2 Cl  1/4H.sub.2 O                                                               24  36.44  (36.41                                                                    3.91  3.86                                                                       23.61   23.55)                      21  Cl                                                                               ##STR43##       235 min. (decomp)  C.sub.10 H.sub.12 N.sub.5                                  O.sub.2 Cl  H.sub.2 O                                                                   7  37.05  (37.33                                                                    4.66  4.33                                                                       21.60   21.52)                      22  Cl                                                                               ##STR44##       175 min. (decomp)  C.sub.10 H.sub.14 N.sub.3                                  O.sub.5 SCl                                                                            47  37.10  (36.93                                                                    4.36  4.40                                                                       12.98   12.80)                      23  Cl                                                                               ##STR45##       230 min. (decomp)  C.sub.7 H.sub.5 N.sub.6 O.sub.4                            Cl       73  30.84  (30.34                                                                    1.85  1.76                                                                       30.83   31.12)                      24  Cl                                                                               ##STR46##       220 min. (decomp)  C.sub.8 H.sub.7 N.sub.4 O.sub.2                            Cl       17  42.40  (42.01                                                                    3.11  3.05                                                                       24.72   24.39)                      __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR47##                                                                                                   Elemental analysis (%)                         Comp'd             m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                             No. R.sup.1                                                                          R.sup.2     Molecular formula                                                                      (%)                                                                              C   H  N                                       __________________________________________________________________________    25  Cl                                                                                ##STR48##  240 min. (decomp)  C.sub.9 H.sub.9 N.sub.4 O.sub.2 Cl                         HCl5/4H.sub.2 O                                                                         8  36.08  (36.03                                                                    4.20  3.94                                                                       18.71   18.44)                          26  Cl                                                                                ##STR49##  185 min. (decomp)  C.sub.8 H.sub.6 N.sub.5 O.sub.4                                     50  35.38  (35.27                                                                    2.23  2.22                                                                       25.78   25.68)                          27  Cl                                                                                ##STR50##  155-158  C.sub.8 H.sub.6 N.sub.5 O.sub.4 Cl                                   5/4H.sub.2 O                                                                           12  32.67  (32.87                                                                    2.91  2.73                                                                       23.81   23.60)                          28  Cl                                                                                ##STR51##  235 min. (decomp)  C.sub.7 H.sub.6 N.sub.5 O.sub.2 Cl                         1/5H.sub.2 O                                                                           14  36.36  (36.74                                                                    2.79  2.71                                                                       30.29   29.96)                          29  Cl                                                                                ##STR52##  255 min. (decomp)  C.sub.9 H.sub.11 N.sub.4 O.sub.2 Cl                         HCl1/10H.sub.2 O                                                                      38  38.48  (38.32                                                                    4.38  4.35                                                                       19.94   19.68)                          30  Cl                                                                                ##STR53##  210 min. (decomp)  C.sub.9 H.sub.11 N.sub.4 O.sub.2 Cl                         TsOH1/10H.sub.2 O                                                                     26  46.12  (45.71                                                                    4.64  4.59                                                                       13.45   13.89)                          31  Br                                                                                ##STR54##  180 min. (decomp)  C.sub.9 H.sub.11 N.sub.4 O.sub.2 Br                         HCl5/4H.sub.2 O                                                                       13  31.23  (31.23                                                                    4.22  4.31                                                                       16.19   16.16)                          32  CH.sub.3                                                                          ##STR55##  250 min. (decomp)  C.sub.10 H.sub.14 N.sub.4 O.sub.2                          HCl1/2H.sub.2 O                                                                        45  44.86  (44.55                                                                    6.02  6.14                                                                       20.93   20.72)                          __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________     ##STR56##                                                                                                    Elemental analysis (%)                        Comp'd              m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                            No. R.sup.1                                                                         R.sup.2       Molecular formula                                                                      (%)                                                                              C   H  N                                      __________________________________________________________________________    33  CN                                                                               ##STR57##    263 min. (decomp)  C.sub.10 H.sub.11 N.sub.5 O.sub.2                          1/4H.sub.2 O                                                                           29  50.52  (50.56                                                                    4.88  4.70                                                                       29.46   29.25)                         34  Cl                                                                               ##STR58##    215 min. (decomp)  C.sub.9 H.sub.12 N.sub.5 O.sub.2                           Cl       22  41.95  (41.64                                                                    4.69  4.75                                                                       27.18   26.80)                         35  Cl                                                                               ##STR59##    205 min. (decomp)  C.sub.10 H.sub.14 N.sub.5 O.sub.2                          Cl  1/6H.sub.2 O                                                                       11  43.72  (43.69                                                                    5.26  5.23                                                                       25.49   25.51)                         36  Cl                                                                               ##STR60##    220 min. (decomp)  C.sub.11 H.sub.16 N.sub.5 O.sub.2                          Cl  4/5H.sub.2 O                                                                       15  44.02  (44.07                                                                    5.91  5.90                                                                       23.33   23.37)                         37  Cl                                                                              --NH(CH.sub.2).sub.2 NH.sub.2                                                               140 min. (decomp)                                                                      70  37.43                                                                            5.23                                                                             23.33                                                      C.sub.7 H.sub.11 N.sub.4 O.sub.2 Cl                                                       (37.44                                                                            5.47                                                                             24.94)                                                     1/3H.sub.2 O                                              38  Br                                                                              --NH(CH.sub.2).sub.2 NH.sub.2                                                               168 min. (decomp)                                                                      46  31.96                                                                            4.21                                                                             21.30                                                      C.sub.7 H.sub.11 N.sub.4 O.sub.2 Br                                                       (31.73                                                                            4.31                                                                             21.32)                                 39  I --NH(CH.sub.2).sub.2 NH.sub.2                                                               145 min. (decomp)                                                                      69  27.11                                                                            3.58                                                                             18.07                                                      C.sub.7 H.sub.11 N.sub.4 O.sub.2 I                                                        (27.01                                                                            3.70                                                                             17.91)                                 40  Cl                                                                              --NH--N(CH.sub.3).sub.2.HCl                                                                 160 min. (decomp)                                                                      94  32.96                                                                            4.74                                                                             21.96                                                      C.sub.7 H.sub.12 N.sub.4 O.sub.2 Cl.sub.2                                                 (32.83                                                                            4.92                                                                             21.93)                                 41  Cl                                                                              --NH(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                      160 min. (decomp)                                                                      23  32.92                                                                            5.98                                                                             17.06                                                      C.sub.9 H.sub.15 N.sub.4 O.sub.2 Cl                                                       (32.90                                                                            6.05                                                                             17.14)                                                     3/2HCl3/2H.sub.2 O                                        __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________     ##STR61##                                                                                                Elemental analysis (%)                            Comp'd          m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                                No. R.sup.1                                                                         R.sup.2   Molecular formula                                                                      (%)                                                                              C   H  N                                          __________________________________________________________________________    42  Cl                                                                              --NH(CH.sub.2).sub.3 NH.sub.2                                                           135 min. (decomp)                                                                       6  40.98                                                                            5.67                                                                             23.89                                                      C.sub.8 H.sub.13 N.sub.4 O.sub.2 Cl                                                       (40.99                                                                            5.89                                                                             23.56)                                                     1/10H.sub.2 O                                                 43  Cl                                                                              --NH(CH.sub.2).sub.2 CN                                                                 205 min. (decomp)                                                                      89  42.03                                                                            3.97                                                                             24.50                                                      C.sub.8 H.sub.9 N.sub.4 O.sub.2 Cl                                                        (42.05                                                                            3.89                                                                             24.35)                                     44  Cl                                                                              --NH(CH.sub.2).sub.3 OH                                                                 167-169  12  41.12                                                                            5.18                                                                             17.98                                                      C.sub.8 H.sub.12 N.sub.3 O.sub.2 Cl                                                       (41.12                                                                            5.43                                                                             18.05)                                     45  Cl                                                                               ##STR62##                                                                              159-160  C.sub.8 H.sub.12 N.sub.3 O.sub.3 Cl                                           38  41.12  (41.17                                                                    5.19  5.35                                                                       17.98   17.93)                             46  Cl                                                                              --NH(CH.sub.2).sub.4 OH                                                                 164-166   2  43.64                                                                            5.70                                                                             16.97                                                      C.sub.9 H.sub.14 N.sub.3 O.sub.3 Cl                                                       (43.57                                                                            5.92                                                                             16.72)                                     47  Cl                                                                               ##STR63##                                                                              228 min. (decomp)  C.sub.8 H.sub.10 N.sub.5 O.sub.2 Cl                        5/4H.sub.2 O                                                                           34  36.10  (36.10                                                                    4.73  4.67                                                                       26.31   26.24)                             48  Br                                                                               ##STR64##                                                                              235 min. (decomp)  C.sub.8 H.sub.10 N.sub.5 O.sub.2 Br                        5/4H.sub.2 O                                                                           25  30.93  (31.05                                                                    4.06  3.96                                                                       22.55   22.70)                             49  I                                                                                ##STR65##                                                                              207 min. (decomp)  C.sub.8 H.sub.10 N.sub.5 O.sub.2 I                         4/5H.sub.2 O                                                                            4  27.49  (27.87                                                                    3.35  3.15                                                                       20.04   19.54)                             50  Cl                                                                               ##STR66##                                                                              260 min. (decomp)  C.sub.8 H.sub.9 N.sub.4 O.sub.2 Cl                         HCl      18  36.38  (36.34                                                                    3.82  3.83                                                                       21.21   20.87)                             __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________     ##STR67##                                                                                                  Elemental analysis (%)                          Comp'd            m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                              No. R.sup.1                                                                          R.sup.2    Molecular formula                                                                      (%)                                                                              C   H  N                                        __________________________________________________________________________    51  Cl                                                                                ##STR68## 244-246  C.sub.8 H.sub.7 N.sub.4 O.sub.2 Cl                                   HCl2/3H.sub.2 O                                                                        64  34.93  (35.14                                                                    3.42  3.36                                                                       20.37   20.07)                           52  Cl                                                                                ##STR69## 195 min. (decomp)  C.sub.7 H.sub.6 N.sub.5 O.sub.2 Cl                         1/5H.sub.2 O                                                                           58  36.36  (35.98                                                                    2.79  2.56                                                                       30.29   30.63)                           53  Cl                                                                                ##STR70## 220 min. (decomp)  C.sub.6 H.sub.7 N.sub.4 O.sub.2 ClS                        HCl      81  26.58  (26.93                                                                    2.97  3.05                                                                       20.66   20.31)                           54  Br                                                                                ##STR71## 235 min. (decomp)  C.sub.6 H.sub.7 N.sub.4 O.sub.2 BrS                        HCl      23  22.84  (22.97                                                                    2.56  2.68                                                                       17.75   17.54)                           55  CH.sub.3                                                                          ##STR72## 160 min. (decomp)  C.sub.7 H.sub.10 N.sub.4 O.sub.2 S                         HClH.sub.2 O                                                                           23  31.29  (31.34                                                                    4.88  5.06                                                                       20.85   20.90)                           56  CN                                                                                ##STR73## 178 min. (decomp)  C.sub.7 H.sub.7 N.sub.5 O.sub.2 S                          HCl      59  32.13  (32.33                                                                    3.08  2.97                                                                       26.76   26.50)                           57  Cl                                                                                ##STR74## 205 min. (decomp)  C.sub.7 H.sub.9 N.sub.4 O.sub.2 ClS                        HCl      93  29.49  (29.61                                                                    3.53  3.60                                                                       19.65   19.70)                           58  Cl                                                                                ##STR75## 200 min. (decomp)  C.sub.8 H.sub.11 N.sub.4 O.sub.2 ClS                        HCl     61  32.12  (32.04                                                                    4.04  4.15                                                                       18.73   18.54)                           59  Cl --NH.sub.2 210      81  33.86                                                                            3.52                                                                             23.69                                                      C.sub.5 H.sub.6 N.sub.3 O.sub.2                                                           (34.28                                                                            3.36                                                                             23.20)                                                     1/10H.sub.2 O                                               __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________     ##STR76##                                                                                                Elemental analysis (%)                            Comp'd          m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                                No. R.sup.1                                                                         R.sup.2   Molecular formula                                                                      (%)                                                                              C   H  N                                          __________________________________________________________________________    60  Cl                                                                              --NHCH.sub.3                                                                            197-199  92  38.01                                                                            4.25                                                                             22.16                                                      C.sub.6 H.sub.8 N.sub.3 O.sub.2 Cl                                                        (37.62                                                                            4.26                                                                             21.94)                                     61  Cl                                                                              --N(CH.sub.3).sub.2                                                                     130 min. (decomp)                                                                      22  41.29                                                                            4.95                                                                             20.64                                                      C.sub.7 H.sub.10 N.sub.3 O.sub.2 Cl                                                       (41.25                                                                            5.01                                                                             20.42)                                     62  Cl                                                                              --NHC.sub.2 H.sub.5                                                                     189-191  52  40.57                                                                            5.06                                                                             20.28                                                      C.sub.7 H.sub.10 N.sub.3 O.sub.2 Cl                                                       (40.60                                                                            5.11                                                                             20.05)                                                     1/5H.sub.2 O                                                  63  Cl                                                                              --N(C.sub.2 H.sub.5).sub.2                                                              155 min. (decomp)                                                                      33  46.66                                                                            6.09                                                                             18.14                                                      C.sub.9 H.sub.14 N.sub.3 O.sub.2 Cl                                                       (46.39                                                                            6.28                                                                             17.95)                                     64  Cl                                                                              --NH(CH.sub.2).sub.2 CH.sub.3                                                           193-195  75  43.43                                                                            5.65                                                                             18.99                                                      C.sub.8 H.sub.12 N.sub.3 O.sub.2 Cl                                                       (43.60                                                                            5.85                                                                             18.98)                                                     1/5H.sub.2 O                                                  65  Cl                                                                              --NHCH(CH.sub.3).sub.2                                                                  185 min. (decomp)                                                                       6  43.25                                                                            5.67                                                                             18.91                                                      C.sub.8 H.sub.12 N.sub.3 O.sub.2 Cl                                                       (43.31                                                                            5.80                                                                             18.86)                                                     1/4H.sub.2 O                                                  66  Cl                                                                              --CH.sub.2 NHCH.sub.3                                                                   256 min. (decomp)                                                                      21  39.54                                                                            5.21                                                                             19.76                                                      C.sub.7 H.sub.10 N.sub.3 O.sub.2 Cl                                                       (39.67                                                                            5.21                                                                             19.42)                                                     1/2H.sub.2 O                                                  67  Cl                                                                              --CH.sub.2 N(CH.sub.3).sub.2                                                            263 min. (decomp)                                                                      67  44.15                                                                            5.56                                                                             19.31                                                      C.sub.8 H.sub.12 N.sub.3 O.sub.2 Cl                                                       (43.83                                                                            5.79                                                                             18.84)                                     68  Cl                                                                               ##STR77##                                                                              255 min. (decomp)  C.sub.6 H.sub.8 N.sub.5 O.sub.2 Cl                         HCl1/10H.sub.2 O                                                                       33  28.16  (28.37                                                                    3.62  3.67                                                                       27.37   27.13)                             __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________     ##STR78##                                                                                                  Elemental analysis (%)                          Comp'd            m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                              No. R.sup.1                                                                         R.sup.2     Molecular formula                                                                      (%)                                                                              C   H  N                                        __________________________________________________________________________    69  Cl                                                                               ##STR79##  200 min. (decomp)  C.sub.7 H.sub.10 N.sub.5 O.sub.2 Cl                        H.sub.2 O                                                                              22  33.68  (33.96                                                                    4.84  4.97                                                                       28.05   27.92)                           70  Cl                                                                               ##STR80##  172 min. (decomp)  C.sub.7 H.sub.10 N.sub.5 O.sub.2 Cl                        HClH.sub.2 O                                                                           42  29.65  (29.39                                                                    4.23  4.58                                                                       24.17   24.48)                           71  Cl                                                                               ##STR81##  189 min. (decomp)  C.sub.8 H.sub.12 N.sub.5 O.sub.2 Cl                        HClH.sub.2 O                                                                           12  32.01  (32.37                                                                    5.04  5.26                                                                       23.33   23.14)                           72  Cl                                                                               ##STR82##  235 min. (decomp)  C.sub.8 H.sub.10 N.sub.5 O.sub.2 Cl                        HCl1/2H.sub.2 O                                                                        25  33.23  (33.26                                                                    4.18  4.09                                                                       24.22  24.13)                            73  Cl                                                                               ##STR83##  220 min. (decomp)  C.sub.7 H.sub.9 N.sub.4 O.sub.2 Cl                         HCl3/5H.sub.2 O                                                                        26  31.86  (31.68                                                                    4.28  4.13                                                                       21.23  21.49                             74  Cl                                                                               ##STR84##  210 min. (decomp)  C.sub.9 H.sub.8 N.sub.3 O.sub.2 Cl                         1/5H.sub.2 O                                                                           24  47.16  (47.63                                                                    3.69  3.70                                                                       18.33  17.92                             75  Cl                                                                               ##STR85##  195 min. (decomp)  C.sub.8 H.sub.7 N.sub.4 O.sub.2 SCl                        HCl2/5C.sub.2 H.sub.5 OH                                                               77  33.71  (33.85                                                                    3.34  3.45                                                                       17.87  17.71                             76  Cl                                                                               ##STR86##  220 min. (decomp)  C.sub.8 H.sub.9 N.sub.4 O.sub.2 SCl                        HCl      80  32.34  (32.46                                                                    3.39  3.40                                                                       18.85  18.98                             __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________     ##STR87##                                                                                                     Elemental analysis (%)                       Comp'd               m.p. (° C.)                                                                     Yield                                                                            Calculated (Found)                           No. R.sup.1                                                                         R.sup.2        Molecular formula                                                                      (%)                                                                              C   H  N                                     __________________________________________________________________________    77  Cl                                                                               ##STR88##     210 min. (decomp)  C.sub.9 H.sub.9 N.sub.4 O.sub.2                            SCl  HCl 87  34.96  (34.90                                                                    3.26  3.31                                                                       18.12  17.98                          78  Cl                                                                               ##STR89##     215 min. (decomp)  C.sub.7 H.sub.6 N.sub.5 O.sub.2                            SCl  HCl 74  28.39  (28.58                                                                    2.38  2.40                                                                       23.65  23.49                          79  Cl                                                                               ##STR90##     223 min. (decomp)  C.sub.12 H.sub.9 N.sub.4 O.sub.2                           SCl  HCl 81  41.75  (41.82                                                                    2.92  2.83                                                                       16.23  16.20                          80  Cl                                                                               ##STR91##     243 min. (decomp)  C.sub.9 H.sub.7 N.sub.4 O.sub.2                            SCl      96  39.93  (40.01                                                                    2.61  3.11                                                                       20.70   20.47)                        81  Cl                                                                               ##STR92##     195 min. (decomp)  C.sub.7 H.sub.9 N.sub.4 O.sub.2                            SCl  2/5H.sub.2 O                                                                      61  32.86  (32.81                                                                    3.86  3.58                                                                       21.89   21.83)                        82  Cl                                                                               ##STR93##     145 min. (decomp)  C.sub.8 H.sub.9 N.sub.6 O.sub.2                            Cl        9  37.44  (37.27                                                                    3.53  3.50                                                                       32.74   33.03)                        83  Cl                                                                               ##STR94##     225 min. (decomp)  C.sub.6 H.sub.7 N.sub.4 O.sub.3                            Cl  H.sub.2 O                                                                           9  30.46  (30.31                                                                    3.83  3.71                                                                       23.68   23.04)                        __________________________________________________________________________

                                      TABLE 11                                    __________________________________________________________________________     ##STR95##                                                                    Comp'd                                                                        No. R.sup.1                                                                          R.sup.2   NMR spectrum (DMSO-d.sub.6) δ                          __________________________________________________________________________    1   Cl                                                                                ##STR96##                                                                              1.66-1.76(4H, m), 2.48-2.60(4H, m), 3.52(2H, s)              2   Br                                                                                ##STR97##                                                                              1.64-1.79(4H, m), 2.52-2.63(4H, m), 3.55(2H, s)              3   I                                                                                 ##STR98##                                                                              1.64-1.79(4H, m), 2.49-2.57(4H, m), 3.57(2H, s)                               11.36(1H, br-s)                                              4   CN                                                                                ##STR99##                                                                              1.75-1.85(4H, m), 2.80-2.88(4H, m), 3.82(2H, s)              5   CH.sub.3                                                                          ##STR100##                                                                             1.67-1.75(4H, m), 1.78(3H, s), 2.45-2.55(4H, m),                              3.38(2H, s)                                                  6   Cl                                                                                ##STR101##                                                                             1.98(2H, quintet, J=7.0Hz), 3.27(4H, t, J=7.0Hz),                             3.46(2H, s), 11.23(1H, br-s)                                 7   Cl                                                                                ##STR102##                                                                             1.00(6H, d, J=5.9Hz), 1.38(2H, m), 1.83(2H, m),                               2.67(2H, m), 3.59(2H, s)                                     8   Cl                                                                                ##STR103##                                                                             1.56(1H, m), 2.01(1H, m), 2.40-2.50(2H, m),                                   2.68-2.78(2H, m), 3.55(2H, s), 4.16(1H, m),  4.82(1H,                         br.s)                                                        9   Cl                                                                                ##STR104##                                                                             1.57-1.82(4H, m), 2.30(1H, q, J=8.0Hz), 2.65(1H, m),                          2.92(1H, m), 3.30(1H, dd, J=11.3, 4.6Hz)  3.44(1H, dd,                        J=11.3, 3.8Hz), 3.55(1H, d, J=5.3Hz),  3.81(1H, d,                            J=5.3Hz), 4.72(1H, br.s), 11.46(1H, br.s)                    __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________     ##STR105##                                                                   Comp'd                                                                        No. R.sup.1                                                                         R.sup.2      NMR spectrum (DMSO-d.sub.6) δ                        __________________________________________________________________________    10  Cl                                                                               ##STR106##  1.55-1.85(4H, m), 2.30(1H, q, J=7.8Hz), 2.65(1H, m),                          2.92(1H, m), 3.25-3.27(1H, m), 3.44(1H, dd, J=11.2,                           3.6Hz), 3.55(1H, d, J=5.3Hz), 3.81(1H, d, J=5.3Hz),                           4.67(1H, br.s), 10.60(1H, br.s), 11.51(1H, br.s)           11  Cl                                                                               ##STR107##  (in D.sub.2 O)  2.14(1H, m), 2.56(1H, m),                                     3.43-3.68(3H, m),  3.84(1H, dd, J=8.1, 12.7Hz),                               4.13(1H, m), 4.37(2H, s)                                   12  Cl                                                                               ##STR108##  2.61(2H, d, J=9.2Hz), 3.01(2H, d, J=9.2Hz),  3.94(2H,                         s), 6.92(1H, s), 11.49(1H, s),  11.57(1H, s)               13  Cl                                                                               ##STR109##  1.32-1.56(6H, m), 2.34-2.46(4H, m), 3.36(2H, s),                              11.11(1H, br, s)                                           14  Br                                                                               ##STR110##  1.31-1.58(6H, m), 2.36-2.53(4H, m), 3.37(2H, s),                              11.39(1H, br.s)                                            15  Cl                                                                               ##STR111##  2.14(3H, s), 2.25-2.45(4H, br.s),  2.45-2.55(4H,                              br.s), 3.33(2H, s)                                         16  Cl                                                                               ##STR112##  2.44-2.47(4H, m), 3.40(2H, s), 3.56-3.60(4H, m),                              10.84(1H, br.s), 11.53(1H, br.s)                           17  Cl                                                                               ##STR113##  1.51-1.66(8H, m) 2.62-2.70(4H, m), 3.54(2H, s)             18  Cl                                                                               ##STR114##  1.45-1.63(10H, m), 2.55-2.65(4H, m), 3.49(2H,              __________________________________________________________________________                       s)                                                     

                                      TABLE 13                                    __________________________________________________________________________     ##STR115##                                                                   Comp'd                                                                        No. R.sup.1                                                                         R.sup.2          NMR spectrum (DMSO-d.sub.6) δ                    __________________________________________________________________________    19  Cl                                                                               ##STR116##      (in CDCl.sub.3)  1.89(4H, quintet, J=3.3Hz),                                  2.68(4H, t, J=3.3Hz),  2.82(2H, m), 2.93(2H, m),                              3.64(2H, s)                                            20  Cl                                                                               ##STR117##      3.46(3H, s), 5.04(2H, s), 7.06(1H, d, J=11.4Hz),                              7.07(1H, d, J=11.4Hz), 8.11(2H, br-s),  11.38(1H,                             br-s), 11.70(1H, s)                                    21  Cl                                                                               ##STR118##      1.26(3H, J=7.2Hz), 3.89(2H, q, J=7.2Hz),  5.06(2H,                            s), 7.07(1H, d, J=2.6Hz),  7.15(1H, d, J=2.6Hz),                              8.19(1H, s), 11.47(1H, s),  11.72(1H, s)               22  Cl                                                                               ##STR119##      1.92(1H, m), 2.26(1H, m), 2.51(1H, m),                                        2.79-2.94(3H, m), 3.18(3H, s), 3.56(2H, s),                                   5.15(1H, m), 10.94(1H, br.s), 11.54(1H, br.s)          23  Cl                                                                               ##STR120##      5.44(2H, s), 8.99(1H, s), 11.55-11.65(1H, br.s),                              11.79(1H, br.s)                                        24  Cl                                                                               ##STR121##      5.17(2H, s), 6.29(1H, dd, J=2.3, 1.5Hz),  7.50(1H,                            d, J=1.5Hz), 7.86(1H, d, J=2.3Hz),  11.53(1H, s),                             11.68(1H, s)                                           25  Cl                                                                               ##STR122##      2.60(3H, s), 5.22(2H, s), 7.54(1H, d, J=2.0Hz),                               7.61(1H, d, J=2.0Hz), 11.77(1H, s)                     __________________________________________________________________________

                                      TABLE 14                                    __________________________________________________________________________     ##STR123##                                                                   Comp'd                                                                        No. R.sup.1                                                                          R.sup.2     NMR spectrum (DMSO-d.sub.6) δ                        __________________________________________________________________________    26  Cl                                                                                ##STR124## 5.54(2H, s), 7.23(1H, d, J=1.2Hz),    7.68(1H, d,                             J=1.2Hz), 11.20-11.60(1H, br.s),  11.70(1H, s)             27  Cl                                                                                ##STR125## 5.18(2H, s), 7.95(1H, d, J=1.3Hz),  8.43(1H, d,                               J=1.3Hz), 11.50(1H, s), 11.70(1H, s)                       28  Cl                                                                                ##STR126## 5.26(2H, s), 8.03(1H, s), 8.64(1H, s), 11.57(1H, s),                          11.70(1H, s)                                               29  Cl                                                                                ##STR127## 2.04(2H, quintet, J=7.6Hz), 2.87(2H, t, J=7.6Hz),                             3.59(2H, t, J=7.6Hz), 4.69(2H, s), 9.40(1H, s)                                9.75(1H, s), 11.46(1H, s), 11.73(1H, s)                    30  Cl                                                                                ##STR128## 2.05(2H, quintet, J=7.7Hz), 2.29(3H, s),  2.87(2H, t,                         J=7.7Hz), 3.60(2H, t, J=7.7Hz), 4.56(2H,  s), 7.11(2H,                        d, J=7.3Hz), 7.47(2H, d, J=7.3Hz)  9.51(1H, br-s),                            11.0-11.8(2H, very br)                                     31  Br                                                                                ##STR129## 2.05(2H, quintet, J=7.4Hz), 2.86(2H, t, J=7.4Hz),                             3.59(2H, t, J=7.4Hz), 4.63(2H, s), 9.29(1H, br-s),                            9.68(1H, br-s), 11.44(1H, s), 11.69(1H, s)                 32  CH.sub.3                                                                          ##STR130## 1.76(3H, s), 2.02(2H, quintet, J=7.6Hz),  2.84(2H, t,                         J=7.6Hz), 3.51(2H, t, J=7.6Hz),  4.55(2H, s)               33  CN                                                                                ##STR131## 2.07(2H, quintet, J=7.6Hz), 2.89(2H, t, J=7.6Hz),                             3.65(2H, t, J=7.6Hz), 4.50(2H, s),                         __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________     ##STR132##                                                                   Comp'd                                                                        No. R.sup.1                                                                         R.sup.2       NMR spectrum (DMSO-d.sub.6) δ                       __________________________________________________________________________    34  Cl                                                                               ##STR133##   2.92(3H, s), 3.57(4H, s), 4.27(2H, s)                     35  Cl                                                                               ##STR134##   1.11(3H, t, J=7.3Hz), 3.35(2H, q, J=7.3Hz),  3.59(4H,                         s), 4.26(2H, s), 9.76(1H, s)                              36  Cl                                                                               ##STR135##   1.15(6H, d, J=6.3Hz), 3.48-3.62(4H, m),  4.04(1H,                             septet, J=6.3Hz), 4.26(2H, s)                             37  Cl                                                                              --NH(CH.sub.2).sub.2 NH.sub.2                                                               2.57-2.72(4H, m), 3.59(2H, s)                             38  Br                                                                              --NH(CH.sub.2).sub.2 NH.sub.2                                                               2.63-2.75(4H, m), 3.58(2H, s)                             39  I --NH(CH.sub.2).sub.2 NH.sub.2                                                               2.58-2.72(4H, m), 3.58(2H, s)                             40  Cl                                                                              --NH--N(CH.sub.3).sub.2.HCl                                                                 3.39(6H, s), 4.67(2H, s), 6.48(2H, s), 11.49(1H, s),                          11.84(1H, s)                                              41  Cl                                                                              --NH(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                      2.83(6H, s), 3.42(4H, s), 4.12(2H, s),                                        8.42(1H, br.s), 11.76(1H, br.s)                           42  Cl                                                                              --NH(CH.sub.2).sub.3 NH.sub.2                                                               1.59(2H, quintet, J=6.1Hz), 2.58(2H, t, J=6.1Hz),                             2.83(2H, t, J=6.1Hz), 3.55(2H, s)                         43  Cl                                                                              --NH(CH.sub.2).sub.2 CN                                                                     2.61(2H, t, J=6.4Hz), 2.74(2H, t, J=6.4Hz),                                   3.66(2H, s), 6.66(1H, br.s)                               __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________     ##STR136##                                                                   Comp'd                                                                        No. R.sup.1                                                                         R.sup.2    NMR spectrum (DMSO-d.sub.6) δ                          __________________________________________________________________________    44  Cl                                                                              --NH(CH.sub.2).sub.3 OH                                                                  1.55(2H, quintet, J=6.6Hz), 2.54(2H, t, J=6.6Hz),                             3.44(2H, t, J=6.6Hz), 3.63(2H, s)                            45  Cl                                                                               ##STR137##                                                                              2.21(3H, s), 2.49-2.53(2H, m), 3.48(2H, t, J=5.4Hz),                          3.52(2H, s), 4.73(1H, br.s), 10.60(1H, br.s),  11.52(1H,                      br.s)                                                        46  Cl                                                                              --NH(CH.sub.2).sub.4 OH                                                                  1.38-1.48(4H, m), 2.46-2.51(2H, m),                                           3.38(2H, t, J=5.6Hz), 3.63(2H, s)                            47  Cl                                                                               ##STR138##                                                                              3.45-3.70(4H, s), 4.26(2H, s)                                48  Br                                                                               ##STR139##                                                                              3.48-3.68(4H, s), 4.25(2H, s)                                49  I                                                                                ##STR140##                                                                              3.45-3.68(4H, m), 4.22(2H, s)                                50  Cl                                                                               ##STR141##                                                                              3.78-3.98(4H, m), 4.60(2H, s) 8.59(1H, s),  10.90(1H,                         br-s), 11.71(1H, s)                                          51  Cl                                                                               ##STR142##                                                                              5.40(2H, s), 7.74(1H, d, J=1.3(Hz),  7.82(1H, d,                              J=1.3Hz), 9.29(1H, s), 11.74(1H, s),  11.78(1H, br-s)        52  Cl                                                                               ##STR143##                                                                              5.45(2H, s), 7.79(1H, s), 8.26(1H, s), 11.69(1H, s),                          11.74(1H, s)                                                 53  Cl                                                                               ##STR144##                                                                              4.35(2H, s), 9.46(4H, br-s), 11.57(1H, br-s),  11.70(1H,                      br-s)                                                        __________________________________________________________________________

                                      TABLE 17                                    __________________________________________________________________________     ##STR145##                                                                   Comp'd                                                                        No. R.sup.1                                                                          R.sup.2     NMR spectrum (DMSO-d.sub.6) δ                        __________________________________________________________________________    54  Br                                                                                ##STR146## 4.33(2H, s), 9.42(4H, br-s), 11.60(1H, br-s),                                 11.66(1H, br-s)                                            55  CH.sub.3                                                                          ##STR147## 1.81(3H, s), 4.26(2H, s), 9.39(4H, br-s),  10.83(1H,                          br-s), 11.18(1H, br-s)                                     56  CN                                                                                ##STR148## 4.33(2H, s)                                                57  Cl                                                                                ##STR149## 2.90(3H, s), 4.32(2H, s), 9.40(1H, br-s),  9.77(1H,                           br-s), 10.20(1H, br-s), 11.51(1H, br-s),  11.67(1H,                           br-s)                                                      58  Cl                                                                                ##STR150## 2.93(3H, s), 3.03(3H, s), 4.27(2H, s),  9.60(1H,                              br-s), 9.94(1H, br-s), 11.53(1H, br-s),  11.67(1H,                            br-s)                                                      59  Cl --NH.sub.2  3.60(2H, s)                                                60  Cl --NHCH.sub.3                                                                              2.27(3H, s), 3.61(2H, s)                                   61  Cl --N(CH.sub.3).sub.2                                                                       2.22(6H, s), 3.33(2H, s), 11.41(1H, br.s)                  62  Cl --NHC.sub.2 H.sub.5                                                                       1.02(3H, t, J=7.1Hz), 2.53(2H, q, J=7.1Hz),                                   3.64(2H, s)                                                63  Cl --N(C.sub.2 H.sub.5).sub.2                                                                0.97(6H, t, J=7.1Hz), 2.55(4H, q, J=7.1Hz),                                   3.49(2H, s)                                                __________________________________________________________________________

                                      TABLE 18                                    __________________________________________________________________________     ##STR151##                                                                   Comp'd                                                                        No. R.sup.1                                                                         R.sup.2    NMR spectrum (DMSO-d.sub.6) δ                          __________________________________________________________________________    64  Cl                                                                              --NH(CH.sub.2).sub.2 CH.sub.3                                                            0.86(3H, t, J=7.3Hz), 1.41(2H, tq, J=7.3, 7.3Hz),                             2.44(2H, t, J=7.3Hz), 3.63(2H, s), 8.05(1H, br.s)            65  Cl                                                                              --NHCH(CH.sub.3).sub.2                                                                   0.99(6H, d, J=6.1Hz), 2.70(1H, sept, J=6.1Hz),                                3.64(2H, s)                                                  66  Cl                                                                              --CH.sub.2 NHCH.sub.3                                                                    2.32(3H, s), 2.67(2H, d, J=6.4Hz),                                            2.79(2H, d, J=6.4Hz)                                         67  Cl                                                                              --CH.sub.2 N(CH.sub.3).sub.2                                                             (in CDCl.sub.3)                                                               2.36(6H, s), 2.71-2.82(4H, m)                                68  Cl                                                                               ##STR152##                                                                              4.29(2H, d, J=5.0Hz), 7.45(3H, br-s),  7.99(1H, t,                            J=5.0Hz), 11.45(1H, br-s),  11.64(1H, br-s)                  69  Cl                                                                               ##STR153##                                                                              2.88(3H, s), 4.48(2H, s), 7.65(4H, s),  11.39(1H, br-s),                      11.63(1H, br-s)                                              70  Cl                                                                               ##STR154##                                                                              2.54(3H, d, J=4.6Hz), 4.28(2H, d, J=5.5Hz),  7.57(1H,                         br-s), 7.74-7.82(2H, m), 11.37(1H, br-s),  11.66(1H, s)      71  Cl                                                                               ##STR155##                                                                              2.77(6H, d, J=4.6Hz), 4.32(2H, d, J=5.6Hz),                                   7.66-7.80(3H, m), 11.29(1H, s), 11.67(1H, s)                 72  Cl                                                                               ##STR156##                                                                              3.62(4H, s), 4.38(2H, d, J=5.6Hz), 8.45(1H, br.s),                            8.69(1H, t, J=5.6Hz), 11.44(1H, s), 11.67(1H,                __________________________________________________________________________                     s)                                                       

                                      TABLE 19                                    __________________________________________________________________________     ##STR157##                                                                   Comp'd                                                                        No. R.sup.1                                                                         R.sup.2        NMR spectrum (DMSO-d.sub.6) δ                      __________________________________________________________________________    73  Cl                                                                               ##STR158##    2.19(3H, s), 4.40(2H, d, J=5.0Hz), 9.13(1H, s),                               9.63(1H, s), 9.86(1H, d, J=5.0Hz), 11.53(1H, s),                              11.73(1H, s)                                             74  Cl                                                                               ##STR159##    4.92(2H, s), 6.04(2H, d, J=1.8Hz),  6.87(2H, d,                               J=1.8Hz), 11.61(2H, br.s)                                75  Cl                                                                               ##STR160##    4.03(2H, s), 7.81(2H, s), 11.30-11.50(1H, br.s),                              11.60(1H, s)                                             76  Cl                                                                               ##STR161##    3.34(4H, s), 4.41(2H, s), 10.50-10.70(1H, br.s),                              11.70(1H, s)                                             77  Cl                                                                               ##STR162##    3.88(3H, s), 3.99(2H, s), 7.77(1H, d, J=1.7Hz),                               7.90(1H, d, J=1.7Hz), 11.41(1H, s), 11.60(1H, s)         78  Cl                                                                               ##STR163##    4.11(2H, s), 8.55(1H, s), 11.33(1H, s),  11.58(1H,                            s)                                                       79  Cl                                                                               ##STR164##    4.35(2H, s), 7.33-7.63(4H, m), 11.63(1H, s)              80  Cl                                                                               ##STR165##    4.31(2H, s), 7.30(1H, t, J=5.0Hz),  8.69(2H, d,                               J=5.0Hz), 11.36(1H, s), 11.61(1H, s)                     __________________________________________________________________________

                                      TABLE 20                                    __________________________________________________________________________     ##STR166##                                                                   Comp'd                                                                        No. R.sup.1                                                                          R.sup.2     NMR spectrum (DMSO-d.sub.6) δ                        __________________________________________________________________________    81  Cl                                                                                ##STR167## 2.77-2.87(3H, br.s), 4.49-4.54(2H, br.s),                                     7.55-8.20(2H, br.s), 10.80-11.00(1H, br.s),                                   11.55-11.65(1H, br.s)                                      82  Cl                                                                                ##STR168## 2.72(3H, d, J=3.6Hz), 4.21(2H, d, J=4.6Hz),                                   7.17-7.35(2H, m), 11.03(1H, s), 11.58(1H, s)               83  Cl                                                                                ##STR169## 4.09(2H, d, J=5.9Hz), 5.86(2H, s),  6.40(1H, t,                               J=5.9Hz), 10.70-10.95(1H, br.s),  11.54(1H,                __________________________________________________________________________                       s)                                                     

    ______________________________________                                        Preparation Example 1 (Antitumor Effect Potentiator)                          ______________________________________                                        Compound 29             25.0   mg                                             Lactose                 8.0                                                   Crystalline cellulose   4.0                                                   Magnesium stearate      1.0                                                   Talc                    1.0                                                   Corn starch             3.5                                                   Hydroxypropyl methylcellulose                                                                         2.5                                                   Tablet                  45.0   mg                                             ______________________________________                                    

In accordance with the above formula, tablets were prepared in a mannerknown per se in the art.

    ______________________________________                                        Preparation Example 2 (Antitumor Effect Potentiator)                          ______________________________________                                        Compound 29            50.0   mg                                              Lactose                85.0                                                   Corn starch            100.0                                                  Hydroxypropyl cellulose                                                                              3.0                                                    Granules               238.0  mg                                              ______________________________________                                    

In accordance with the above formula, granules were prepared in a mannerknown per se in the art.

    ______________________________________                                        Preparation Example 3 (Antitumor Effect Potentiator)                          ______________________________________                                        Compound 29           50.0   mg                                               Lactose               24.0                                                    Crystalline cellulose 13.0                                                    Magnesium stearate    1.0                                                     Capsule               88.0   mg                                               ______________________________________                                    

In accordance with the above formula, capsules were prepared in a mannerknown per se in the art.

    ______________________________________                                        Preparation Example 4 (Antitumor Agent)                                       ______________________________________                                        5-Trifluoromethyl-2'-deoxyuridine                                                                     12.5   mg                                             (F.sub.3 dThd)                                                                Compound 29             25.0   mg                                             Lactose                 8.0                                                   Crystalline cellulose   3.5                                                   Magnesium stearate      1.0                                                   Talc                    1.0                                                   Corn starch             3.5                                                   Hydroxypropyl methylcellulose                                                                         2.5                                                   (Per tablet)            57.0   mg                                             ______________________________________                                    

In accordance with the above formula, tablets were prepared in a mannerknown per se in the art.

    ______________________________________                                        Preparation Example 5 (Antitumor Agent)                                       ______________________________________                                        5-Trifluoromethyl-2'-deoxyuridine                                                                     12.5   mg                                             (F.sub.3 dThd)                                                                Compound 29             50.0   mg                                             Lactose                 85.0                                                  Corn starch             100.0                                                 Hydroxypropyl cellulose 2.5                                                   (Per bag)               250.0  mg                                             ______________________________________                                    

In accordance with the above formula, granules were prepared in a mannerknown per se in the art.

    ______________________________________                                        Preparation Example 6 (Antitumor Agent)                                       ______________________________________                                        5-Trifluoromethyl-2'-deoxyuridine                                                                     12.5   mg                                             (F.sub.3 dThd)                                                                Compound 29             50.0   mg                                             Lactose                 24.0                                                  Crystalline cellulose   12.5                                                  Magnesium stearate      1.0                                                   (Per capsule)           100.0  mg                                             ______________________________________                                    

In accordance with the above formula, capsules were prepared in a mannerknown per se in the art.

Test 1 (Thymidine Phosphorylase Inhibiting Effects)

Inhibitory effects of some uracil derivatives (I) or salts thereof onthymidine phosphorylase were each determined by measuring the formationof [6-³ H]thymine from [6-³ H]thymidine in the below-described manner.

Namely, reacted at 37° C. for 5 minutes were 0.05 ml of a 3 mM aqueoussolution of thymidine (which contained 74 Bq/ml of [6-³ H]thymidine),0.05 ml of a 0.5 M potassium phosphate buffer (pH 7.4), 0.05 ml of asolution of one of the test compounds at one of various concentrationsor purified water as a control, and 0.1 ml of a solution of thymidinephosphorylase obtained from human placenta in a highly purified form,0.25 ml in total. Immediately after the reaction, the reaction mixturewas heated for 2 minutes in a boiling water bath of 100° C. to terminatethe reaction, followed by centrifugation at 3000 rpm for 10 minutes.Subsequent to the centrifugation, a portion (10 μl) of the resultantsupernatant was spotted on a silica gel 60F₂₅₄ plate of 2.0×10 cm andwas then dried in air. The plate was placed in a developer bath whichwas filled with chloroform-methanol-acetic acid (v/v/v, 17:3:1), so thatthe spot was developed to a position of about 8 cm. The silica gel platewas pulled out and then dried in air. Under a UV lamp, a position (R_(f)0.46) of [6-³ H]thymine was marked. Silica gel was scraped off from theposition by a stainless steel spatula and then placed in a vial forliquid scintillation. One hundred microliters of 2 N HCl were added tomoisten the silica gel, whereby [6-³ H]thymine was liberated from thegel. Thereafter, 10 ml of scintillator ("AQUASOL-II", product ofAmersham International plc) were added, followed by thorough agitationwith a stirrer. Radioactivity was then measured by a scintillationcounter ("WALLAC SYSTEM 1410", manufactured by Pharmacia AB).

Inhibitory activities of the test compound were determined by thefollowing formula: ##EQU1##

The concentration of each test solution which inhibited 50% of theamount of [6-³ H]thymine formed by thymidine phosphorylase is shown asIC₅₀ (μM) in Table 21.

To compare inhibitory activities, IC₅₀ s of 6-amino-5-chlorouracil,6-amino-5-bromouracil, 6-aminothymine, acyclothymidine and3-cyano-2,6-dihydroxypyrimidine were also measured and calculated.

                  TABLE 21                                                        ______________________________________                                        Compound No. or Compound Name                                                                      IC.sub.50 (μM)                                        ______________________________________                                         1                   2.2                                                       2                   0.51                                                      3                   1.3                                                       6                   2.6                                                      20                   0.24                                                     29                   0.035                                                    32                   0.12                                                     33                   0.017                                                    34                   0.046                                                    47                   0.013                                                    48                   0.030                                                    50                   1.2                                                      51                   1.0                                                      53                   0.35                                                     56                   0.10                                                     57                   0.15                                                     68                   0.27                                                     73                   1.5                                                      6-Amino-5-chlorouracil                                                                             12                                                       6-Amino-5-bromouracil                                                                              19                                                       6-Aminothymine       100                                                      Acyclothymidine      >1000                                                    3-Cyano-2,6-dihydroxypyridine                                                                      130                                                      ______________________________________                                    

Test 2 (Antitumor Effects)

(a) Preparation of the test solution I:

F₃ dThd was suspended in portions of a 0.5% solution of hydroxypropylmethylcellulose so that its concentrations became 5.0 mg/ml and 10.0mg/ml. They were separately agitated by stirrers at room temperature forabout 20 minutes and then subjected to ultrasonic treatment for 5minutes under ice cooling, whereby drug solutions [test solutions(1),(2)] were obtained for the single administration of F₃ dThd.

(b) Preparation of test solutions II:

F₃ dThd was suspended in a 0.5% solution of hydroxypropylmethylcellulose so that its concentration became 7.5 mg/ml. To portionsof the suspension, one of some uracil derivatives (1) or a salt thereof(Compounds 2, 29, 47 and 48) was added so that its concentrations became6.9, 7.0, 6.9 and 7.5 mg/ml. The resultant mixtures were separatelyagitated at room temperature for about 20 minutes by stirrers and thensubjected to ultrasonic treatment under ice cooling, whereby mixedsolutions [test solutions (3) to (6)] according to the present inventionwere obtained.

(c) Test:

Nude-mouse-transplanted human tumor sections of about 2 mm square weresubcutaneously transplanted to axillary fossae of nude mouse of 4 to 5weeks old. When an estimated tumor volume as determined by V=1/2×L(major axis)×(minor axis)×Q (thickness) reached about 150 mm³, a controlgroup and treated groups were set so that the averages and standarddeviations (S.D.) of tumors in the individual treated groups became asequal as possible. Administration of the drugs was then started.

The administration was conducted by orally administering the testsolutions (1) to (6) in an amount of 1.0 ml per 100 g of the body weightof each nude mouse once a day for 14 days. The tumor-bearing rats in thecontrol group were orally administered only with a 0.5% solution ofhydroxypropyl methylcellulose.

Upon an elapsed time of 24 hours after the final administration of eachdrug, the above-described estimated tumor volume (V) was determined. Inaccordance with the below-described formula, a tumor size reduction rate(%) was then determined and is shown in

                  TABLE 22                                                        ______________________________________                                         ##STR170##                                                                   ______________________________________                                    

                  TABLE 22                                                        ______________________________________                                                                         Tumor size                                   Test                     Dose*   reduction                                    solution Drug            (mg/kg) rate (%)                                     ______________________________________                                        1        F.sub.3 dThd    50      27                                           2                        100     50                                           3        F.sub.3 dThd + Comp'd 2                                                                       75      66                                           4        F.sub.3 dThd + Comp'd 29                                                                      75      61                                           5        F.sub.3 dThd + Comp'd 47                                                                      75      56                                           6        F.sub.3 dThd + Comp'd 48                                                                      75      46                                           ______________________________________                                         *in terms of the amount of F.sub.3 dThd.                                 

Test 3 (Antitumor Effects)

(a) Preparation of test solutions I:

F₃ dThd was suspended in portions of a 0.5% solution of hydroxypropylmethylcellulose so that its concentrations became 1.25, 2.5, 5.0, 7.5and 10.0 mg/ml. Thy were separately agitated by stirrers at roomtemperature for about 20 minutes and then subjected to ultrasonictreatment for 5 minutes under ice cooling, whereby drug solutions [testsolutions (1) to (5)] were obtained for the single administration of F₃dThd.

(b) Preparation of test solutions II:

F₃ dThd was suspended in portions of a 0.5% solution hydroxypropylmethylcellulose so that its concentrations became 1.25, 2.5, 5.0, 7.5and 10 mg/ml. Compound 29 was added to the individual suspensions sothat its concentrations became 0.23, 0.46, 0.93, 1.39 and 1.85 mg/ml,respectively. The resultant mixtures were separately agitated at roomtemperature for about 20 minutes by stirrers and then subjected toultrasonic treatment for 5 minutes under ice cooling, whereby F₃dThd-Compound 29 (molar ratio: 1:0.2) mixed solutions [test solutions(6) to (10)] were obtained.

(c) Preparation of test solutions III:

F₃ dThd-Compound 29 (molar ratio: 1:0.5) mixed solutions [test solutions(11) to (15)] were obtained in a similar manner as the preparation ofthe above test solutions except that the amount of Compound 29 was setat 0.58, 1.16, 2.31, 3.47 and 4.63 mg/ml.

(d) Preparation of test solutions IV:

F₃ dThd-Compound 29 (molar ratio: 1:1) mixed solutions [test solutions(16) to (20)] were obtained in a similar manner as the preparation ofthe above test solutions except that the amount of Compound 29 was setat 1.16, 2.31, 4.63, 6.94 and 9.25 mg/ml.

(e) Preparation of test solutions V:

F₃ dThd-Compound 29 (molar ratio: 1:2) mixed solutions [test solutions(21) to (25)] were obtained in a similar manner as the preparation ofthe above test solutions except that the amount of Compound 29 was setat 2.31, 4.63, 9.25, 13.88 and 18.51 mg/ml.

(f) Preparation of test solutions VI:

F₃ dThd-Compound 29 (molar ratio: 1:5) mixed solutions [test solutions(26) to (30)] were obtained in a similar manner as the preparation ofthe above test solutions except that the amount of Compound 29 was setat 5.78, 11.57, 23.14, 34.70 and 46.27 mg/ml.

(g) Test:

A test was conducted in a similar manner as Test 2 except for the use ofthe test solutions (1) to (30).

Further, the body weight was periodically measured from the 24th hourafter the last day of the drug administration to determine body weightchanges (BWCs) relative to the body weight before the initiation of thedrug administration. In accordance with the following formula, atherapeutic index (TI) was then determined and is shown in Table 23.##EQU2##

                  TABLE 23                                                        ______________________________________                                                                              Therapeutic                             Test  Drug       Dose*   ED.sub.50                                                                           BWC.sub.-10                                                                          index                                   solution                                                                            (molar ratio)                                                                            (mg/kg) (mg/kg)                                                                             (mg/kg)                                                                              BWC.sub.-10 /ED.sub.50                  ______________________________________                                        1     Administration                                                                           12.5    26.9  73.8   2.7                                     2     of         25.0                                                         3     F.sub.3 dThd alone                                                                       50.0                                                         4                75.0                                                         5                100.0                                                        6     F.sub.3 dThd                                                                             12.5    5.6   >100   >17.9                                   7     +          25.0                                                         8     Compound 29                                                                              50.0                                                         9     (1:0.2)    75.0                                                         10               100.0                                                        11    F3dThd     12.5    7.9   >100   >12.7                                   12    +          25.0                                                         13    Compound 29                                                                              50.0                                                         14    (1:0.5)    75.0                                                         15               100.0                                                        16    F.sub.3 dThd                                                                             12.5    7.8   >100   >12.8                                   17    +          25.0                                                         18    Compound 29                                                                              50.0                                                         19    (1:1)      75.0                                                         20               100.0                                                        21    F.sub.3 dThd                                                                             12.5    8.7   >100   >11.5                                   22    +          25.0                                                         23    Compound 29                                                                              50.0                                                         24    (1:2)      75.0                                                         25               100.0                                                        26    F.sub.3 dThd                                                                             12.5    10.1  >100   >9.9                                    27    +          25.0                                                         28    Compound: 29                                                                             50.0                                                         29    (1:5)      75.0                                                         30               100.0                                                        ______________________________________                                         *in terms of the amount of F.sub.3 dThd.   Test 4 (Antitumor Effects)    

A test was conducted in a similar manner as Test 3 except for the use ofCompound 2 instead of Compound 29. The results are shown in Table 24.

                  TABLE 24                                                        ______________________________________                                                                              Therapeutic                             Test  Drug       Dose*   ED.sub.50                                                                           BWC.sub.-10                                                                          index                                   solution                                                                            (molar ratio)                                                                            (mg/kg) (mg/kg)                                                                             (mg/kg)                                                                              BWC.sub.-10 /ED.sub.50                  ______________________________________                                        1     Administration                                                                           12.5    60.0  103    1.7                                     2     of         25.0                                                         3     F.sub.3 dThd alone                                                                       50.0                                                         4                75.0                                                         5                100.0                                                        6     F.sub.3 dThd                                                                             12.5    43.0  87     2.0                                     7     +          25.0                                                         8     Compound 2 50.0                                                         9     (1:0.2)    75.0                                                         10               100.0                                                        11    F3dThd     12.5    35.0  82     2.3                                     12    +          25.0                                                         13    Compound 2 50.0                                                         14    (1:0.5)    75.0                                                         15               100.0                                                        16    F.sub.3 dThd                                                                             12.5    12.0  85     7.1                                     17    +          25.0                                                         18    Compound 2 50.0                                                         19    (1:1)      75.0                                                         20               100.0                                                        21    F.sub.3 dThd                                                                             12.5    10.5  48     4.6                                     22    +          25.0                                                         23    Compound 2 50.0                                                         24    (1:2)      75.0                                                         25               100.0                                                        26    F.sub.3 dThd                                                                             12.5    16.5  43     2.0                                     27    +          25.0                                                         28    Compound: 2                                                                              50.0                                                         29    (1:5)      75.0                                                         30               100.0                                                        ______________________________________                                         *in terms of the amount of F.sub.3 dThd.                                 

Test 5 (Antitumor Effects)

(a) Preparation of test solutions I:

5-Fluoro-2'-deoxyuridine (FdUrd) was suspended in portions of a 0.5%solution of hydroxypropyl methylcellulose so that its concentrationsbecame 0.5 mg/ml and 1.0 mg/ml, respectively. The suspensions wereseparately agitated by stirrers at room temperature for about 20 minutesand then subjected to ultrasonic treatment under ice cooling for 5minutes, whereby test solutions (1) and (2) were obtained.

(b) Preparation of test solutions II:

Compound 2 and Compound 29 were separately suspended in portions of thetest solution (1) so that their concentrations became 0.83 mg/ml and0.81 mg/ml, respectively. The suspensions were separately agitated bystirrers at room temperature for about 20 minutes and then subjected toultrasonic treatment under ice cooling for 5 minutes, whereby testsolutions (3) and (4) were obtained.

(c) Preparation of test solutions III:

Compound 2 and Compound 29 were separately suspended in portions of thetest solution (2) so that their concentrations became 4.15 mg/ml and4.05 mg/ml, respectively. The suspensions were separately agitated bystirrers at room temperature for about 20 minutes and then subjected toultrasonic treatment under ice cooling for 5 minutes, whereby testsolutions (5) and (6) were obtained.

(c) Test:

S-180 cells (1×10⁷ cells) were subcutaneously transplanted to the backsof ICR male mice of 5 weeks old. After an elapsed time of 24 hours fromthe transplant, one of the above-described test solutions (1) to (6) wasorally administered once a day in an amount of 0.1 ml per 10 g of thebody weight of the mouse for 7 days. A 0.5% solution of hydroxypropylmethylcellulose alone was orally administered to each tumor-bearingmouse in a control group. On the 10th day after the transplant of thetumor, the mouse was sacrificed, and the tumor was enucleated and itsweight was measured. In accordance with the following formula, a tumorsize reduction rate (%) was determined and is shown in Table 25.##EQU3##

                  TABLE 25                                                        ______________________________________                                                                        Tumor size                                    Test     Drug           Dose*   reduction                                     solution (molar ratio)  (mg/kg) rate (%)                                      ______________________________________                                        1        FdUrd          5       10.5                                          2                       10      24.4                                          3        FdUrd + Comp'd 2                                                                             5       46.4                                                   (1:1)                                                                5        FdUrd + Comp'd 2                                                                             5       48.2                                                   (1:5)                                                                4        FdUrd + Comp'd 29                                                                            5       58.8                                                   (1:1)                                                                6        FdUrd + Comp'd 29                                                                            5       47.2                                                   (1:5)                                                                ______________________________________                                         *in terms of the amount of FdUrd.   Capability of Exploitation in Industr

The uracil derivatives of the formula (1) and their salts have themerits that they have extremely great thymidine phosphorylase inhibitingactivities compared with conventionally-known thymidine phosphorylaseinhibitors and substantially enforce antitumor effects of2'-deoxypyrimidine nucleosides. Accordingly, antitumor effectpotentiator and antitumor agent according to the present invention haveextremely high utility.

What is claimed is:
 1. A uracil derivative represented by the following formula (1'): ##STR171## wherein R¹ is selected from the group consisting of chlorine, bromine, iodine, cyano and a lower alkyl group; and R² represents an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyan group; a (lower alkyl) amidino group; a group --CH₂ N(R^(a))R^(b) in which R^(a) and R^(b) may be the same or different and each represents a hydrogen atom or a lower alkyl group or R^(a) and R^(b) may form a pyrrolidine ring together with the nitrogen atom to which R^(a) and R^(b) are bonded; a group --NH--(CH₂)_(m) --Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group or a cyano group, and m stands for an integer of from 0 to 3; a group NR^(c) (CH₂)_(n) --OH in which R^(c) represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4; a group --X--Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups; or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group, with the proviso that R¹ and R² are not a bromine atom and an amino group, respectively, at the same time; or a salt thereof.
 2. The uracil derivative or salt thereof according to claim 1, wherein in the formula (1'), the group represented by R² is an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group; or a (lower alkyl)amidino group.
 3. The uracil derivative or salt thereof according to claim 1, wherein in the formula 1', the group represented by R² is selected from the group consisting of an amidinothio, N¹ -methylamidinothio, N¹,N² -dimethylamidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2,3-dimethylguanidino and an acetoamidino group.
 4. The uracil derivative or salt thereof according to claim 2, wherein in the formula 1', the group represented by R² is selected from the group consisting of an amidinothio, N¹ -methylamidinothio, N¹,N² -dimethylamidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2,3-dimethylguanidino and an acetoamidino group.
 5. The uracil derivative or salt thereof according to claim 1, wherein in the formula 1', the group represented by R¹ is selected from the group consisting of chlorine, bromine, and cyano, and the group represented by R² is an amidinothio or 1-guanidino group.
 6. The uracil derivative or salt thereof according to claim 1, which is selected from the group consisting of 2-(5-chlorouracil-6-ylmethyl)-isothiourea hydrochloride, 2-(5-cyanouracil-6-ylmethyl)isothiourea hydrochloride and 5-chloro-6-(1-guanidino)methyluracil hydrochloride.
 7. A pharmaceutical composition comprising:a uracil derivative represented by the following formula (1): ##STR172## wherein R¹ is selected from the group consisting of chlorine, bromine, iodine, cyano and a lower alkyl group; and R² represents an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group; a (lower alkyl)amidino group; a group --CH₂ N(R^(a))R^(b) in which R^(a) and R^(b) may be the same or different and each represents a hydrogen atom or a lower alkyl group or R^(a) and R^(b) may form a pyrrolidine ring together with the nitrogen atom to which R^(a) and R^(b) are bonded; a group --NH--(CH₂)_(m) --Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group or a cyano group, and m stands for an integer of from 0 to 3; a group NR^(c) (CH₂)_(n) --OH in which R^(c) represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4; a group --X--Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups; or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; or a salt thereof; and a pharmaceutically acceptable carrier.
 8. The pharmaceutical composition according to claim 7, wherein in the formula (1), the group represented by R² is an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each by substituted by a lower alkyl group; a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each by substituted by a lower alkyl or cyano group; or a (lower alkyl)amidino group.
 9. The pharmaceutical composition according to claim 7, wherein in the formula (1), the group represented by R² is selected from the group consisting of an amidinothio, N¹ -methylamidinothio, N¹,N² -dimethyl-amidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2,3,-dimethylguanidino and an acetoamidino group.
 10. The pharmaceutical composition according to claim 8, wherein in the formula (1), the group represented by R² is selected from the group consisting of an amidinothio, N¹ -methylamidinothio, N¹,N² -dimethyl-amidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2,3,-dimethylguanidino and an acetoamidino group.
 11. The pharmaceutical composition according to claim 7, wherein in the formula (1), the group represented by R¹ is selected from the group consisting of chlorine, bromine, and cyano, and the group represented by R² is an amidinothio or 1-guanidino group.
 12. The pharmaceutical composition according to claim 7, wherein the compound represented by the formula (1) is selected from the group consisting of 2-(5-chlorouracil-6-ylmethyl)isothiourea hydrochloride, 2-(5-cyanouracil-6-ylmethyl)isothiourea hydrochloride and 5-chloro-6-(1-guanidino)methyluracil hydrochloride.
 13. A method for potentiating an antitumor effect of an antitumor agent containing a 2'-deoxypyrimidine nucleoside, which comprises administering to a patient an effective amount of a uracil derivative represented by the following formula (1): ##STR173## wherein R¹ is selected from the group consisting of chlorine, bromine, iodine, cyano and a lower alkyl group; and R² represents an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group; a (lower alkyl)amidino group; a group --CH₂ N(R^(a))R^(b) in which R^(a) and R^(b) may be the same or different and each represents a hydrogen atom or a lower alkyl group or R^(a) and R^(b) may form a pyrrolidine ring together with the nitrogen atom to which R^(a) and R^(b) are bonded; a group --NH--(CH₂)_(m) --Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group, or a cyano group, and m stands for an integer of from 0 to 3; a group NR^(c) (CH₂)_(n) --OH in which R^(c) represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4; a group --X--Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups; or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; or a salt thereof.
 14. A therapeutic method for treating cancer, which comprises administering to a patient in need of treatment an effective amount of a uracil derivative represented by the following formula ##STR174## wherein R¹ is selected from the group consisting of chlorine, bromine, iodine, cyano and a lower alkyl group; and R² represents an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group; a (lower alkyl)amidino group; a group --CH₂ N(R^(a))R^(b) in which R^(a) and R^(b) may be the same or different and each represents a hydrogen atom or a lower alkyl group or R^(a) and R^(b) may form a pyrrolidine ring together with the nitrogen atom to which R^(a) and R^(b) are bonded; a group --NH--(CH₂)_(m) --Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group or a cyano group, and m stands for an integer of from 0 to 3; a group NR^(c) (CH₂)_(n) --OH in which R^(c) represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4; a group --X--Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups; or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; or a salt thereof; and a 2'-deoxypyrimidine nucleoside. 